CN106986856A - It is used as 4 { [(ylmethyl of pyridine 3) amino carbonyl] amino } Benzosulfone derivatives of the NAMPT inhibitor for treating diseases such as cancer - Google Patents

It is used as 4 { [(ylmethyl of pyridine 3) amino carbonyl] amino } Benzosulfone derivatives of the NAMPT inhibitor for treating diseases such as cancer Download PDF

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Publication number
CN106986856A
CN106986856A CN201610866074.2A CN201610866074A CN106986856A CN 106986856 A CN106986856 A CN 106986856A CN 201610866074 A CN201610866074 A CN 201610866074A CN 106986856 A CN106986856 A CN 106986856A
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China
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alkyl
aryl
compound
formula
heteroaryl
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CN201610866074.2A
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Chinese (zh)
Inventor
K.W.贝尔
T.R.鲍迈斯特
A.J.巴克梅尔特
K.H.克洛德菲尔特
韩炳松
林间
D.J.雷诺兹
C.C.史密斯
王忠国
郑孝章
袁步伟
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Genentech Inc
Forma Therapeutics Inc
Forma TM LLC
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Genentech Inc
Forma Therapeutics Inc
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Publication of CN106986856A publication Critical patent/CN106986856A/en
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Abstract

The present invention relates to for the compound and composition that suppress NAMPT, their synthesis, using and antidote.Embodiment of the present invention provides formula III A compound.

Description

It is used as the 4- { [(pyridine -3- of the NAMPT inhibitor for treating diseases such as cancer Base-methyl) amino carbonyl] amino } benzene-sulfone derivative
The application is that (Application No. 201180053248.9, international application no is PCT/ to Chinese invention patent application US2011/050320, the applying date is September in 2011 2, entitled " to be used as the NAMPT for treating diseases such as cancer 4- { [(pyridin-3-yl-methyl) amino carbonyl] amino } benzene-sulfone derivative of inhibitor ") divisional application.
The cross reference of related application
Application claims U.S. Provisional Patent Application 61/379,812 and 61/379,819 (was carried on the 3rd in September in 2010 Hand over), U.S. Provisional Patent Application 61/386,037 and 61/386,044 (being submitted for 24th in September in 2010), the U.S. it is temporarily special Profit application 61/478,995 (being submitted on April 26th, 2011) and U.S. Provisional Patent Application 61/480,423 are (in April, 2011 29 days submit) priority, the full content of all these patent applications is incorporated herein to be used as reference.
Technical field
The present invention relates to the compound and composition for suppressing nicotinamide phosphoribosyl transferase (" NAMPT "), it Synthesis, using and antidote.
Background technology
NADH (NAD) is in cellular energy metabolism and cellular signal transduction (cellular Signaling played an important role in).In energetic supersession, the chemical property of pyridine ring allows NAD by a large amount of dehydrogenase catalyzed Hydride transfer reaction in easily receive and provide electronics.
The preparation of compounds (include several subclass) as nicotinamide adenine nucleotides formation inhibitor and they Patent application WO00/50399, W097/48695, W097/48696, W097/ are had been described in as the purposes of antitumor agent 48397th, in WO99/31063, WO99/31060, WO99/31087, WO99/31064, WO00/50399 and WO03/80054.
By one kind ((E)-N- [4- (l- benzoyl piperidine -4- bases) butyl] -3- (pyridine -3- in these inhibitor Base)-acrylamide, also referred to as AP0866, FK866, WK175 or WK22.175, and hereinafter referred to as FK866 is [international non-special Have title]) especially it is described as anticancer in the literature.FK866 can be used for treating the disease for involving deregulated Apoptosis Such as cancer.Have confirmed in the prior art, FK866 interference NADH (it is also known, and hereafter Referred to as NAD) biosynthesis, and the cell death of inducing cell apoptosis, and without the influence of any DNA damage.
In addition, FK866 ((E)-N- [4- (l- benzoyl piperidine -4- bases) butyl] -3- (pyridin-3-yl) acrylamide) The inducing cell apoptosis in HepG2 cells, and there is no material impact (Hasmann M, Schemainda to cellular energy metabolism I.FK866,a Highly Specific Noncompetitive Inhibitor of Nicotinamide Phosphoribosyltransferase,Represents a Novel Mechanism for Induction of Tumor Cell Apoptosis.Cancer Res 2003；63:7436-7442.[PubMed:14612543]).It not causes immediately Cytotoxicity, but suppress NAMPT and exhaust NAD cells, this shows that FK866 can be for synthesizing NAD's by niacinamide The promising medicine of cancer cell.The crystal structure of NAMPT-FK866 compounds shows that compound combines the nicotinoyl in NAMPT Amine binding site, which is sentenced, suppresses its activity.FK866 in hamster kidney cell cancer model test, and confirm display it is antitumor, Anti-rotation move and anti-angiogenesis activity (Drevs J, et al.Antiangiogenic potency of FK866/K22.175, a new inhibitor of intracellular NAD biosynthesis,in murine renal cell carcinoma.Anticancer Res 2003；23:4853-4858.[PubMed:14981935]).
In mouse mammary cancer model, the FK866 also delay of induced tumor growth and the enhancings of tumor radiosensitivity, and Reduced with the dose dependent of NAD levels, pH and energy state.In antineoplastic l- methyl-3-nitros-l- nitrosoguanidines (MNNG) have also been observed that FK866's is chemical quick in the cell death in THP-1 and K562 Leukemia Cell Lines of induction Change effect (Pogrebniak A, et al.Chemopotentiating effects of a novel NAD biosynthesis inhibitor,FK866,in combination with antineoplastic agents.Eur J Med Res 2006；11:313-321.[PubMed:17052966]).
GMX1777 effect is have rated in xenograft models, and is measured by liquid chromatography/mass spectrography GMX1778 Pharmacokinetic Characteristics and its influence (Beauparlant to NADH cellular level P.,et al.Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777.Anticancer Drugs.2009 Jun；20(5):346- 54)。
GMX1777 is the prodrug of GMX1778 water-soluble intravenous administration, and the GMX1778 is Gemin X from LEO Pharma is in perhaps available (LEO numberings：Respectively EB1627 and CHS828).These compounds and other substituted cyanoguanidines Structure with table 1.The compound not cyanoguanidines of the present invention.
Table 1：
The substituted cyanoguanidines of pharmacological effect with determination：
The CHS 828 of A cytotoxicities；
12g compounds described in B potassium channel openerses Pinacidil (pinacidil) (B1) and Perez-Medrano etc. (B2)；With
C histamine-II receptor antagonists Cimetidines (cimetidine) (come from Lovborg et al.BMC Research Notes 2009 2:114doi:10.1186/1756-0500-2-114)。
Recently, CHS-828 is identified as NAMPT inhibitor (Olesen UH, et al.Anticancer agent CHS-828inhibits cellular synthesis of NAD.Biochem Biophys Res Commun 2008； 367:799-804.[PubMed:18201551]).CHS-828 has shown that the compound effectively suppresses the swollen of wide scope Cell growth in oncocyte system, although the detailed mechanism of CHS-828 this inhibition still do not determine (Ravaud A, et al.Phase I study and guanidine kinetics of CHS-828,a guanidine-containing compound,administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study.Eur J Cancer 2005；41:702-707.[PubMed:15763645]).FK866 and CHS-828 is at present in the clinical test for treatment of cancer.
Suppressing NAMPT medicine has numerous purposes.
The development for lacking consumingly influence T and bone-marrow-derived lymphocyte of NAMPT expression.By using the mutation of this protein Form and the pharmacological inhibitors (FK866) fully characterized, author confirm that NAMPT stress period regulation cell life in genetoxic Depositing the ability of power needs its enzymatic activity.Altogether, these data confirm thats, NAMPT is participated in genetoxic/oxidative stress Cell resistance, and it can assign immune system cell survival ability (Rongvaux, A., et during stressful situation such as inflammation al.The Journal of Immunology,2008,181:4685-4695)。
NAMPT also can have influence to high glucose level, oxidative stress and the aging of endothelium (EC).It is also believed that NAMPT may be such that Hypertrophic people EC can resist the oxidative stress of aging and high glucose, and fruitful using unnecessary Glucose support replicate life-span and angiogenic activity.
The content of the invention
One aspect of the present invention provide the compound for the NAMPT approach in mammal, composition, kit and Antidote, wherein the compound has compound of formula I and its pharmaceutical salts, solvate, ester and isomers：
Wherein：
Ar1For aryl, heteroaryl or Heterocyclylalkyl, wherein the hetero atom number of each heteroaryl and Heterocyclylalkyl be 1, 2 or 3, and be independently selected from N, S or O, the wherein each aryl, heteroaryl and Heterocyclylalkyl can be independently by aryl, miscellaneous in addition Aryl or Heterocyclylalkyl substitution or with aryl, heteroaryl or Heterocyclylalkyl condense, still in addition wherein described aryl, heteroaryl and Any one in Heterocyclylalkyl is unsubstituted or is optionally independently substituted by one or more substituents that the substituent can phase With or it is different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2、-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkene Base, alkynyl, alkoxy-,-aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkane Base ,-N (R3)-C (O)-aryl ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,- Aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl, condition are when being S or be different when two adjacent ring hetero atoms are different For O；
X is straight or branched C1-C6Alkyl；
L is selected from NHC (O) NH, OC (O) NH, NHC (O) O, OCH2C(O)NH、C(O)NH、NHC(S)NH、OC(S)NH、NHC (S)O、OCH2C (S) NH or C (S) NH；
A is aryl, heteroaryl, Heterocyclylalkyl or C3To C8Cycloalkyl, wherein each aryl, heteroaryl, Heterocyclylalkyl With cycloalkyl be unsubstituted or optionally independently by 1,2,3 or 4 substituents replace, the substituent may be the same or different and Be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkane Base) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, Alkoxy-,-aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-aryl ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,- C (O)-aryl ,-S (O)-aryl and heteroaryl；
Q is C (O), S (O), S (O)2；
R3For H, alkyl or aryl alkyl-；
Z is 0,1 or 2；And
Or：
(i)(a)R1Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched hydroxyl Base C1To C4Alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, Cycloalkyl-alkyl-, hydroxy alkyl-, alkoxyalkyl-, miscellaneous spiro cycloalkyl group and miscellaneous spiroheterocyclic alkyl, wherein described in above-mentioned part The hetero atom of heteroaryl and Heterocyclylalkyl is independently selected from one or more N, O and S, and condition is that two adjacent ring hetero atoms are different When be S or be asynchronously O, wherein R in addition1Can be unsubstituted or optionally independently by (i) one or more substituents Substitution, the substituent may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (ammonia Base) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、- CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxy alkane Base)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl Oxo) alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,- N(R3)-C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-it is miscellaneous Cycloalkyl ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed； And (b) R2Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched hydroxyl C1To C4 Alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl alkane Base-, hydroxy alkyl-, alkoxyalkyl-, miscellaneous spiro cycloalkyl group and miscellaneous spiroheterocyclic alkyl, wherein heteroaryl described in above-mentioned part and The hetero atom of Heterocyclylalkyl is independently selected from one or more N, O and S, condition be when two adjacent ring hetero atoms are different for S or It is asynchronously O, in addition wherein R2It can be unsubstituted or optionally independently replaced by (i) one or more substituents, institute Substituent is stated to may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alcoxyl Base-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed；
Or (ii) R1And R2C is formed together with the N that they are connected is shown in formula3-C8Heterocyclylalkyl, C3-C8Heterocycle alkene Base, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl, wherein each described miscellaneous Cycloalkyl, heterocycloalkenyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl optionally show them containing one or more remove in formula Hetero atom outside the N connected, the hetero atom is selected from N, S and O, and condition is that two adjacent ring hetero atoms are S when different Or be asynchronously O, the wherein each Heterocyclylalkyl, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, heterocycle alkene in addition Base, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl are unsubstituted or are optionally independently substituted by one or more substituents, described Substituent may be the same or different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alcoxyl Base-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl；
Condition is that the compound of formula I is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
Another aspect of the present invention provides compound of formula I and its pharmaceutical salts, solvate, ester and isomers,
Wherein, X, L, Q, Ar1With A as defined in Formulas I, and R1Selected from H, straight or branched C1To C7Alkyl, straight chain or Side chain C1To C7Alkoxy, straight or branched hydroxyl C1To C4Alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkane Base-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl-alkyl-, hydroxy alkyl-, alkoxyalkyl-, spiroheterocyclic alkyl and Miscellaneous spiroheterocyclic alkyl, wherein the hetero atom of the heteroaryl and Heterocyclylalkyl described in above-mentioned part is independently selected from one or more N, O And S, condition, which is, to be S when two adjacent ring hetero atoms are different or is asynchronously O, in addition wherein R1Can be it is unsubstituted or Optionally independently replaced by (i) one or more substituents, the substituent may be the same or different, and be independently selected from deuterium, halogen, Cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2、-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) Epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkane Base amino, dialkyl amido, (Heterocyclylalkyl oxo) alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,- C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylidene Two epoxides (for example, methylene-dioxy) ,-Heterocyclylalkyl ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,- Heterocyclylalkyl ,-aryl or heteroaryl-condensed；And
R2Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched hydroxyl C1Extremely C4Alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl Alkyl-, hydroxy alkyl-, alkoxyalkyl-, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl, wherein the heteroaryl described in above-mentioned part One or more N, O and S are independently selected from the hetero atom of Heterocyclylalkyl, condition is that two adjacent ring hetero atoms are S when different Or be asynchronously O, in addition wherein R2It can be unsubstituted or optionally independently replaced by (i) one or more substituents, The substituent may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkane Epoxide-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed；
Condition is that the compound of formula I is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
Another aspect of the present invention provides compound of formula I, wherein X, L, Q, Ar1With A as defined in Formulas I：
Wherein R1And R2C is formed together with the N that they are connected is shown in formula3-C8Heterocyclylalkyl, C3-C8It is heterocycloalkenyl, thick Bicyclic heterocycles alkyl, fused tricyclic heterocycles alkyl, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl are closed, wherein each heterocycle alkane Base, heterocycloalkenyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl optionally show that they connect containing one or more remove in formula Hetero atom outside the N connect, the hetero atom is selected from N, S and O, for S or not when condition is two adjacent ring hetero atoms differences Simultaneously for O, in addition wherein each Heterocyclylalkyl, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, heterocycloalkenyl, Spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl are unsubstituted or are optionally independently substituted by one or more substituents, the substitution Base may be the same or different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,- CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z、 Alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl oxygen Base) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) alkyl-, aryl Epoxide, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-virtue Base ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-Heterocyclylalkyl ,-aryl And heteroaryl；
Condition is that the compound is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyrroles Pyridine -4- ylmethyls) thiocarbamide.
Another aspect of the present invention provides the compound for the NAMPT approach in mammal, composition, kit and conciliate Toxic agent, the compound has Formula II compound and its pharmaceutical salts, solvate, ester, prodrug and isomers：
Ar1-(CHR)n-L-Ar2-X-R1
II
Wherein
Ar1For aryl, heteroaryl or Heterocyclylalkyl, wherein the hetero atom number of each heteroaryl and Heterocyclylalkyl be 1, 2 or 3, and be independently selected from N, S or O, the wherein each aryl, heteroaryl and Heterocyclylalkyl can be independently by aryl, miscellaneous in addition Aryl or Heterocyclylalkyl substitution or with aryl, heteroaryl or Heterocyclylalkyl condense, still in addition wherein described aryl, heteroaryl and Any one in Heterocyclylalkyl is unsubstituted or is optionally independently substituted by one or more substituents that the substituent can phase With or it is different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2、-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkene Base, alkynyl, alkoxy-,-aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkane Base ,-N (R3)-C (O)-aryl ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,- Aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl, condition are when being S or be different when two adjacent ring hetero atoms are different For O；
R is H, straight or branched C1-C6Alkyl or aryl alkyl；
N is 0,1,2,3 or 4；
L is selected from NHC (O) NH, OC (O) NH, NHC (O) O, OCH2C(O)NH、C(O)NH、NHC(S)NH、OC(S)NH、NHC (S)O、OCH2C (S) NH or C (S) NH, condition is that then n is 0 when L is C (O) NH；
Ar2For aryl, heteroaryl, Heterocyclylalkyl or C3To C8Cycloalkyl, wherein each aryl, heteroaryl, heterocycle alkane Base and cycloalkyl be unsubstituted or by 1,2,3 or 4 substituents replace, the substituent may be the same or different and be independently selected from Deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, alkoxy-,- Aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-virtue Base ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl；
X is S, S (O), S (O)2, O or C (O)；
R1For cycloalkyl ,-CHzF3-z, aryl, Heterocyclylalkyl, heteroaryl, alkyl ,-alkenyl ,-alkynyl, (aryl) alkyl-, (heteroaryl) alkyl-or (Heterocyclylalkyl) alkyl-, (i) the wherein each cycloalkyl, aryl, Heterocyclylalkyl, heteroaryl and alkane Base be unsubstituted or by 1,2,3,4 or 5 substituents replace, the substituent may be the same or different and be independently selected from deuterium, halogen Element, cyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2、-C(O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl ,-alkenyl ,-alkynyl, alkoxy-, hydroxyl ,-alkyl hydroxyl Base, aryloxy-or (alkoxyalkyl) amino-,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,-S (O)2- alkyl ,-S (O)2- virtue Base ,-S (O)2-CF3,-C (O) N (alkyl)2,-C (O) alkyl ,-NH-C (O)-alkyl ,-NH-C (O)-aryl, methylene-dioxy and Heteroaryl, (ii) in addition wherein each the cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl can additional optional with independent selection Aryl, heteroaryl, Heterocyclylalkyl or Cycloalkylfused；
R3For H, alkyl or aryl alkyl-；
Z is 0,1 or 2；
Condition be the compound of formula I be not 3- { 1- [(4- methoxyphenyls) sulfonyl] piperidin-4-yl } -1- (pyridine - 3- ylmethyls) urea, or
1- (4- Phenoxyphenyls) -3- (pyridin-3-yl methyl) thiocarbamide.
Another aspect of the present invention provides the compound for the NAMPT approach in mammal, composition, kit and conciliate Toxic agent, the compound is derived from Formulas I and II compounds and with formula III and its pharmaceutical salts, solvate, ester and isomers：
Wherein：
Ar1For comprising 1, the heteroatomic 5-12 unit's heteroaryls that 2,3 or 4 are independently selected from N, S or O, wherein the heteroaryl Base is unsubstituted or by one or more RaSubstitution, the RaSelected from-NH2, oxo, halogen, haloalkyl ,-NH (CO) O- alkane Base ,-C (O) NH2With 3,4- dihydroxy -5- methyltetrahydrofurans；And wherein described heteroaryl can include it is one or more by institute The N- oxides that the N atomic components of heteroaryl are formed are stated, condition is S when being two adjacent ring hetero atoms differences or is asynchronously O；
Ar2For aryl or comprising 1, heteroatomic 5 or 6 unit's heteroaryls that 2,3 or 4 are independently selected from N, S or O；
R is H, straight or branched C1-C6Alkyl or aryl alkyl；
R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkyl, hydroxy alkyl ,-S (O)2Alkane Base ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl；
Haloalkyl,
Cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；Wherein：
(i) each cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl for it is unsubstituted or by 1,2,3,4 or 5 substitutions Base replaces, and the substituent is identical or different and is independently selected from：
Deuterium, halogen, cyano group, alkyl, hydroxyl, hydroxy alkyl, hydroxy alkoxy base, cyanoalkyl, haloalkyl, alkenyl, alkynes Base, alkoxy, alkyl alkoxy, halogenated alkoxy, aryl alkenyl-, aryloxy, benzyl epoxide, oxo ,-(CH2)q- NRbRc、-(CH2)q-CONRbRc、-S(O)2- alkyl ,-S (O)2- aryl ,-S (O)2NH- alkyl ,-S (O)2N (alkyl)2、-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3,-C (O) alkyl ,-C (O) aryl ,-C (O) alkenyl aryl ,-C (O) O- alkyl ,-NH-C (O) alkyl ,-NH-C (O) aryl, methylene-dioxy ,-(CH2)qCycloalkyl, cycloalkyl alkoxy-, aryl, aryl alkyl-,- (CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl,
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, haloalkyl, alkyl halides One or more of epoxide, oxo, cyano group, alkyl, haloalkyl or alkoxy replace, and；
(ii) aryl optionally also with independent selection of each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, miscellaneous Aryl, Heterocyclylalkyl or the ring of Cycloalkylfused formation two or three cyclic groups, two rings or three cyclic groups can by halogen, cyano group, One or more of alkyl or alkoxy replace；
R2For O or it is not present,
RbAnd RcIt is independently selected from H, alkyl, hydroxy alkyl, alkoxy, aryl, alkoxyalkyl ,-S (O)2Alkyl and cycloalkanes Base, or RbAnd Rc5 or 6 circle heterocycles alkyl are formed together with the nitrogen-atoms that can be connected with them, wherein the Heterocyclylalkyl can contain There are one or more additional heteroatoms selected from N, S or O；
N is 0 or 1；
Q is 0,1 or 2；
Condition be the formula III compound be not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
Another embodiment of the present invention provides formula III compound, wherein Ar1It is 1, Ar for pyridine radicals, n2For phenyl and described Formula is formula III A：
Wherein R1And RaThe condition as defined in formula III be the compound be not N- [4- (phenyl sulfonyl) phenyl]- N'- (3- pyridylmethyls) urea, N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamides or 4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
Another aspect of the present invention is formula III A compounds and its pharmaceutical salts, wherein：
RaTo be multiple and may be selected from amino, oxo, halogen, halo (C1-C6) alkyl ,-NH (CO) O- (C1-C6) alkyl and-C (O)NH2；And wherein described pyridine radicals can include the N- oxides formed by its N atomic component；
R1For-NR3R4, wherein R3For H, C1-C6- alkyl or-S (O)2(C1-C6) alkyl, and R4For (C1-C6) alkyl, hydroxyl Base (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl；
Halo (C1-C6) alkyl,
Cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；
Wherein：
The each cycloalkyl, aryl or heteroaryl be unsubstituted or by 1,2,3,4 or 5 substituents replace, it is described Substituent is identical or different and is independently selected from following：
Halogen, cyano group, (C1-C6) alkyl, hydroxyl, hydroxyl (C1-C6) alkyl, hydroxyl (C1-C6) alkoxy, halo (C1-C6) Alkyl, (C1-C6) alkoxy, (C1-C6) alkyl (C1-C6) alkoxy, halo (C1-C6) alkoxy, aryl (C2-C6) alkenyl-, Aryloxy, benzyl epoxide, oxo ,-(CH2)q-NRbRc、-(CH2)q-CONRbRc、-S(O)2-(C1-C6) alkyl ,-S (O)2NH- (C1-C6) alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3、-C(O)(C1-C6) alkyl ,-C (O) aryl ,-C (O) (C2-C6) alkene Base aryl ,-C (O) O- (C1-C6) alkyl ,-(CH2)qCycloalkyl, cycloalkyl (C1-C6) alkoxy-, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl,
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, halo (C1-C6) alkyl, Halo (C1-C6) alkoxy, oxo, cyano group, (C1-C6) alkyl, halo (C1-C6) alkyl or (C1-C6) one in alkoxy or Multiple substitutions；
RbAnd RcIt is independently selected from H, (C1-C6) alkyl, hydroxyl (C1-C6) alkyl, (C1-C6) alkoxy, aryl, (C1-C6) alkane Epoxide (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl and (C3-C6) cycloalkyl, or RbAnd RcThe nitrogen that can be connected with them is former Son forms 5 or 6 circle heterocycles alkyl together, wherein the Heterocyclylalkyl can contain one or more extra miscellaneous originals selected from N, S or O Son；
Q is 0 or 1；And
Condition is that the formula III A compounds are not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea,
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide, or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
Another aspect of the present invention is provided in the subject (for example, people) of needs by suppressing NAMPT to treat disease Method, methods described passes through the compound of the invention or pharmaceutical preparation to snibject's effective dose.
Another aspect of the present invention is provided treats, prevents, suppresses or eliminates described by suppressing the NAMPT in patient The method of disease or illness in patient, the chemical combination at least one disclosure that methods described passes through drug treatment effective dose Thing, wherein the disease or illness are selected from cancer, oophoroma, breast cancer, uterine cancer, colon cancer, cervical carcinoma, lung cancer, prostatitis Gland cancer, cutaneum carcinoma, carcinoma of urinary bladder, cancer of pancreas, leukaemia, lymthoma, Hodgkin's disease, viral infection, human immunodeficiency virus, hepatitis It is virus, herpesviral, herpe simplex, inflammatory disorder, IBS, inflammatory bowel disease, rheumatoid arthritis, asthma, slow It is property obstructive disease of lung, osteoarthritis, osteoporosis, dermatitis, atopic dermatitis, psoriasis, systemic lupus erythematosus, many Hair property hardening, psoriatic arthritis, ankylosing spondylitis, graft versus host disease(GVH disease), Alzheimer disease, cerebrovas-cularaccident, move Pulse atherosclerosis, diabetes, glomerulonephritis, metabolic syndrome, non-small cell lung cancer, ED-SCLC, Huppert's disease, Leukaemia, lymthoma, squamous cell carcinoma, kidney, urethra and carcinoma of urinary bladder, head and neck cancer, brain and central nervous system cancer.
Another preferred embodiment is the pharmaceutical preparation of the medicinal compound comprising the present invention, and it is carried after the mankind are delivered medicine to For tumor load and/or the reduction of transfer.The pharmaceutical preparation can be administered by oral way or other suitable modes.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose with The method for the treatment of oophoroma in the subject (for example, mankind) needed.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose with The method for the treatment of colon cancer in the subject (for example, mankind) needed.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose with The method for the treatment of breast cancer in the subject (for example, mankind) needed.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose with The method for the treatment of leukaemia in the subject (for example, mankind) needed.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose with The side of colon cancer is treated in the subject (for example, mankind) needed before or after surgical discectomy and/or radiotherapy Method.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose, including The auxiliary treatment (including or without dexamethasone) of nausea is treated, is cut in the subject (for example, mankind) of needs in surgery Except the method for the treatment of cancer before or after art and/or radiotherapy.
Another embodiment be by the compound of the invention or pharmaceutical preparation to snibject's effective dose, including Using one or more kinds of other therapeutic agents or the auxiliary treatment of their pharmaceutical salts, needs subject (for example, people Class) in before or after surgical discectomy and/or radiotherapy treating cancer method.This other therapeutic agent it is non- Limitative examples include cytotoxic agent (such as, but not limited to, DNA interaction agent (such as cis-platinum or Doxorubicin))； Taxanes (such as taxotere, PTX)；Topoisomerase II inhibitors (such as Etoposide)；Topoisomerase I inhibitor (such as Irinotecan (or CPT-11), Irinotecan parenteral solution (camptostar), or Hycamtin)；Tubulin is mutual Agent (such as taxol, Docetaxel or Epothilones)；Hormone preparation (such as TAM)；Thymidylate synthetase presses down Preparation (such as 5 FU 5 fluorouracil or 5-FU)；Antimetabolite (such as methotrexate (MTX))；Alkylating agent (such as Temozolomide, ring phosphorus Acid amides)；Farnesyl protein transferase inhibitor (such as, SARASARTM(4- [2- [4- [the bromo- 8- chloro- 6 of (11R) -3,10- two, 11- dihydro -5H- benzos [5, -6] cycloheptadiene simultaneously [1,2-b] pyridine -11- bases -] -1- piperidyls] -2- oxoethyls] -1- piperazines Pyridine-formamide, or SCH66336), for pyrrole method Buddhist nun (Or R115777, from Janssen Pharmaceuticals), L778,123 (farnesyl protein transferase inhibitors, from Merck＆Company, Whitehouse Station, N.J.), (farnesyl protein transferase inhibitors, from Bristol-Myers Squibb of BMS 214662 Pharmaceuticals,Princeton,N.J.)；Signal transduction inhibitor (for example,(come from Astra Zeneca Pharmaceuticals,England)、(EGFR kinase inhibitor), EGFR antibody (for example, C225)、(C-abl kinase inhibitors, from Novartis Pharmaceuticals, East Hanover, N.J.)；Interferon, for example(coming from Merck＆Company),(coming from Merck＆Company)；Swash Extract for treating is combined；Aromatase combination product；Cytarabine, doxorubicin, cyclophosphamide and gemcitabine.
Other anticancer (also referred to as antitumor) agent include but is not limited to uracil mustard (Uracil mustard), mustargen (Chlormethine), ifosfamide (Ifosfamide), melphalan (Melphalan), Chlorambucil (Chlorambucil), pipobroman (Pipobroman), tretamine (Triethylenemelamine), triethylene sulphur For phosphamide (Triethylenethiophosphoramine), busulfan (Busulfan), BCNU (Carmustine), Lomustine (Lomustine), streptozotocin (Streptozocin), Dacarbazine (Dacarbazine), floxuridine (Floxuridine), cytarabine (Cytarabine), 6-MP (6-Mercaptopurine), 6-thioguanine (6- Thioguanine), fludarabine phosphate (Fludarabine phosphate), oxaliplatin (oxaliplatin), folinic acid Calcium (leucovirin), oxaliplatin (oxaliplatin) (From Sanofi-Synthelabo Pharmaceuticals, France), Pentostatin (Pentostatine), vincaleukoblastinum (Vinblastine), vincristine (Vincristine), eldisine (Vindesine), bleomycin (Bleomycin), actinomycin D (Dactinomycin), daunorubicin (Daunorubicin), Doxorubicin (Doxorubicin), epirubicin (Epirubicin), idarubicin (Idarubicin), mithramycin (Mithramycin), deoxycoformycin (Deoxycoformycin), Mitomycin-C (Mitomycin-C), L-ASP (L-Asparaginase), for Ni Bo Glycosides (Teniposide), the female alcohol of 17 alpha-acetylenes (17 α-Ethinylestradiol), diethylstilbestrol (Diethylstilbestrol), Testosterone (Testosterone), metacortandracin (Prednisone), Fluoxymesterone (Fluoxymesterone), dromostanolone propionate (Dromostanolone propionate), Testolactone (Testolactone), megestrol acetate (Megestrolacetate), methylprednisolone (Methylprednisolone), methyltestosterone (Methyltestosterone), sprinkle Ni Songlong (Prednisolone), fluoxyprednisolone (Triamcinolone), Chlorotrianisene (Chlorotrianisene), hydroxyl are pregnant Ketone (Hydroxyprogesterone), aminoglutethimide (Aminoglutethimide), Estramustine (Estramustine), vinegar Sour Medroxyprogesterone (Medroxyprogesteroneacetate), Leuprorelin (Leuprolide), Flutamide (Flutamide), Toremifene (Toremifene), Goserelin (goserelin), cis-platinum (Cisplatin), carboplatin (Carboplatin), hydroxycarbamide (Hydroxyurea), amsacrine (Amsacrine), procarbazine (Procarbazine), rice Tuo Tan (Mitotane), mitoxantrone (Mitoxantrone), levamisol (Levamisole), NVB (Navelbene), Anastrozole (Anastrazole), Letrozole (Letrazole), capecitabine (Capecitabine), Raloxifene (Reloxafine), Droloxifene (Droloxafine), hexamidine (Hexamethylmelamine), Avastin (Avastin), Trastuzumab (herceptin), hectogram husky (Bexxar),Ze Walin (Zevalin), Trisenox (Trisenox), Xeloda (Xeloda), vinorelbine (Vinorelbine), porfimer (Porfimer), Chinese mugwort Bit thinks (Erbitux), liposome (Liposomal), thiotepa (Thiotepa), hemel (Altretamine), American and French Logical sequence (Melphalan), trastuzumab (Trastuzumab), Letrozole (Lerozole), fulvestrant (Fulvestrant), according to Xi Meitan (Exemestane), ifosfamide (Ifosfomide), Rituximab (Rituximab), C225 and bank handkerchief This (Campath), 5 FU 5 fluorouracil (5-fluorouracil) and Calciumlevofolinate (leucovorin), comprising or without 5- HT3Acceptor inhibitor is (for example, Dolasetron (dolansetron), Granisetron (granisetron), Ondansetron (ondansetron)), comprising or without dexamethasone (dexamethasone).
If being formulated as fixed dosage, then this combination product using in herein described dosage range (or this Known to art personnel) the compounds of this invention and the other medicines activating agent in its dosage range or treatment.For example, It has been found that CDC2 inhibitor olomoucine (olomucine) is cooperateed with terms of inducing cell apoptosis with known cytotoxic agent Effect (J.Cell Sci., (1995) 108,2897).When combination preparation is improper, the compounds of this invention can also resist with known Cancer or cytotoxic agent order of administration.In any therapeutic alliance, the order of administration of the present invention is not limited；The change of formula (I) Compound can be administered before or after the administration of known anticancer or cytotoxic agent.For example, cyclin-dependent kinase The cellular cytoxicity activity of inhibitor Flavopiridol (flavopiridol) is influenceed by the order of administration with anticancer.Cancer Research,(1997)57,3375.This technology is in the technical scope of those skilled in the art and attending doctor.
It is such as sub- by the way that fluid (such as water), medullary loop diuretics, one or more kinds of chemotherapeutics or antitumor agent is administered Calcium Folinate-SF and fluorouracil, and NACT agent (such as Filgrastim and erythropoietin(EPO)), or foregoing any combinations, Any preceding method can be expanded.
Another embodiment is by the pharmaceutical preparation to the snibject present invention, to the subject of needs (for example, people Class) method of the compounds of this invention is administered.
Another embodiment is by mixing at least one medicinal compound of the present invention and optional one or more kinds of medicines With additive or excipient, the method for preparing the pharmaceutical preparation of the present invention.
For preparing pharmaceutical composition from compound of the present invention, inert pharmaceutical carrier can be solid or liquid Body.Solid form preparations include powder agent, tablet, discrete particles, capsule, cachet and suppository.Powder agent and tablet can be wrapped Active component containing about 5 to about 95%.Suitable solid carrier is known in the art, for example, magnesium carbonate, magnesium stearate, cunning Stone, sugar or lactose.Tablet, powder agent, cachet and capsule can be used as the solid dosage forms suitable for being administered orally.It is medicinal The preparation method of the example of carrier and various compositions can be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.,Easton,Pa。
Liquid form preparation includes solution, supensoid agent and emulsion.It can be mentioned that as example for parenteral injection Water either water-propylene glycol solution agent or addition sweetener and opacifying agent be used for oral solution, supensoid agent and emulsion. Liquid form preparation may also comprise the solution for intranasal administration.
Aerosol suitable for suction may include the solid of solution and powder type, and it can be with pharmaceutical carrier such as inertia compressed gas Body such as nitrogen is combined.
Also include being intended to change into liquid form preparation before it will use for oral or parenteral Solid form preparations.This liquid form includes solution, supensoid agent and emulsion.
The compounds of this invention also can transdermal delivery.Transdermal composition can take cream, lotion, aerosol and/or emulsion Form, and can be included in the transdermal patch of matrix or storage type, for this purpose, it is commonly used in the art 's.
The compounds of this invention also can subcutaneous delivery.
Preferably, by compound is oral or intravenous administration.
Preferably, the pharmaceutical preparation is unit dosage form.In this format, the preparation is subdivided into suitable size Unit dose, containing appropriate active component quantity, for example, realizing the effective dose for wishing purpose.
According to concrete application, the reactive compound quantity in the unit dose of preparation can change or from about 1mg to about 1000mg, preferably from about 1mg are adjusted to about 500mg, more preferably from about 1mg to about 250mg more preferably from about 1mg to about 25mg Section.
With the seriousness of the illness for the treatment of the need for depending on patient, the actual dose used can be changed.For specific feelings Condition determines suitable dosage within the skill of the art.For convenience, can be on demand by total daily dose on daytime Separate and portioning administration.
The dosage and frequency of the compounds of this invention and/or its pharmaceutical salts adjust the judgement according to attending doctor, its In view of the age of such as patient, illness and size and the factor of the seriousness of the symptom for the treatment of.For being administered orally, generally The daily dose scheme of recommendation can be about 1mg/ to about 500mg/, preferably 1mg/ to 200mg/, with 2-4 parts of portioning agent Amount.
Another aspect of the present invention is the medicine comprising the compounds of this invention and cellular rescue agents (rescuing agent) Composition.In some embodiment of the present invention, cellular rescue agents are selected from niacinamide, nicotinamide mononucleotide (NMN) and cigarette Acid.
Definition
Contain below with use, unless otherwise specified, following term should being interpreted as having in entire disclosure when above Justice.If having lacked a definition, then be applicable usual definition well known by persons skilled in the art.
" patient " includes humans and animals.
" mammal " refers to people and other mammals.
Term " inhibitor " refers to the molecule such as compound, medicine for blocking or otherwise disturbing specific bioactivity Thing, enzyme activator or hormone.
Term " effective dose " or " therapeutically effective amount " refer to the enough reagents for providing desired biological result.The result can For any other desired change of the reduction and/or mitigation of the sign, symptom or reason of disease, or biosystem.For example, controlling " effective dose " for treating purposes is the amount of composition, and the composition includes this Shen clinically significantly alleviated for needing to provide disease The compound that please be disclose.In any case, appropriate " effective " amount can use normal experiment by those of ordinary skill in the art Determine.Therefore, statement " effective dose ", which typically refers to active material, has the amount of therapeutic effect.In the case of the present invention, activity Material is the inhibitor of the formation of nicotinamide phosphoribosyl transferase (NAMPT).
Term " treatment (treat) " used in this application or " treatment (treatment) " and term " prevention (prevent) " It is synonymous, it is intended that to represent delaying, preventing disease from developing and/or reducing the tight of the symptom of development or expected development for disease development Principal characteristic.Therefore, these terms include improving existing disease symptomses, prevent other symptom, improve or prevent the potential of symptom Metabolism reason, suppress obstacle or disease, for example, retardation obstacle or advancing of disease, mitigate obstacle or disease, cause obstacle or Illness or stopping disease or the symptom of obstacle caused by disease regression, mitigation disease or obstacle.
" pharmaceutically acceptable " or " pharmacologically be subjected to " refers to not biologically or other side is not wished substantially The material of prestige, i.e. can be by the administering substances in individual, without causing any substantially undesirable biotic influence or to have Harmful mode and any component of the composition comprising this material interact.
" carrier mass " or the also referred to as material of " excipient " include any commonly employed excipient in pharmacy, and Ying Ji Selected in the release profile property of compatibility and desired formulation.Exemplary carrier material includes, for example, adhesive, suspending Agent, disintegrant, filler, surfactant, solubilizer, stabilizer, lubricant, wetting agent, diluent etc.." pharmaceutically can phase Appearance carrier mass " may include, for example, Arabic gum, gelatin, cataloid, calcium glycerophosphate, calcium lactate, dextrin-wheat Bud sugar complexing agent, glycerine, magnesium silicate, casein sodium, soybean lecithin, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, tristearin Acyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch etc..See, e.g., Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa。1975。
Term " subject " used in this application includes mammal and nonmammalian.The example of mammal include but It is not limited to the other any member of mammal：People, non-human primates such as chimpanzee, and other apes and monkey class；Farming is moved Thing such as ox, horse, sheep, goat, pig；Domestic animal such as rabbit, dog and cat；Laboratory animal, including rodent such as rat, mouse and Cavy etc..The example of nonmammalian includes but is not limited to bird, fish etc..In one embodiment of the invention, mammal For people.
" alkyl " used in this application refers to 1-10 or 1-6 (C1-C6) carbon atom straight or branched saturation Chain.Representative saturated alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl isophthalic acids-propyl group, 2- methyl -2- Propyl group, 2- methyl-l- butyl, 3- methyl isophthalic acids-butyl, 2- methyl -3- butyl, 2,2- dimethyl-l- propyl group, 2- methyl-l- penta Base, 3- methyl-1-pentenes base, 4- methyl-l- amyl groups, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 2,2- Dimethyl-l- butyl, 3,3- dimethyl-l- butyl, 2- ethyl -1- butyl, butyl, isobutyl group, the tert-butyl group, n-pentyl, isoamyl Base, neopentyl, n-hexyl etc., and longer alkyl, such as heptyl and octyl group.Alkyl can be unsubstituted or substituted.Contain The alkyl for having 3 or more carbon atoms can be straight chain, side chain or ring-type." low alkyl group " used in this application refers to Alkyl with 1-6 carbon atom.
" alkenyl " used in this application includes nonbranched or branched hydrocarbon chain, wherein with one or more double bonds.Alkene The double bond of base can or conjugation non-conjugated with another unsaturated group.Illustrative alkenyl includes but is not limited to (C2-C8) or (C2-C6) Alkenyl, such as vinyl (ethylenyl), vinyl, pi-allyl, cyclobutenyl, pentenyl, hexenyl, butadienyl, pentadiene Base, hexadienyl, 2- ethyl hexyls alkenyl, 2- propyl group -2- cyclobutenyls, 4- (2- methyl -3- butylene)-pentenyl etc..Alkenyl can be It is unsubstituted or substituted.
Term " hydroxy alkyl " refers to alkyl as defined above, wherein at least one hydrogen atom of the alkyl is replaced by hydroxyl Generation.The example of hydroxy alkyl includes but is not limited to the methyl that wherein one or more hydrogen atoms are substituted by OH, ethyl, propyl group, different Propyl group, isobutyl group, sec-butyl, the tert-butyl group, amyl group or n-hexyl, and the application illustrated below by embodiment that A little hydroxy alkyls.
" alkynyl " used in this application includes nonbranched or branched hydrocarbon chain, wherein with one or more three keys.Alkynes Three keys of base can or conjugation non-conjugated with another unsaturated group.Suitable alkynyl includes but is not limited to (C2-C6) alkynyl, such as Acetenyl, propinyl, butynyl, pentynyl, hexin base, methylpropynyl, 4- methyl-l- butynyls, 4- propyl group-valerylene Base, 4- butyl -2- hexin bases etc..Alkynyl can be unsubstituted or substituted.
Term " haloalkyl " refers to alkyl as defined above, wherein at least one hydrogen atom of the alkyl is former by halogen Son is substituted, preferably fluorine or chlorine, most preferably fluorine.The example of haloalkyl includes but is not limited to wherein one or more hydrogen atom quilts Methyl, ethyl, propyl group, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group or n-hexyl that CI, F, Br or I atom are substituted, And those haloalkyls that the application is illustrated below by embodiment.It is preferred that haloalkyl include single fluorine, difluoro Or trifluoromethyl, single fluorine, difluoro or trifluoroethyl or single fluorine, difluoro or trifluoro propyl, such as 3,3,3- trifluoro propyls, 2- fluorine second Base, 2,2,2- trifluoroethyls, methyl fluoride, trifluoromethyl.
Term " trifluoromethyl ", " sulfonyl " and " carboxyl " include CF respectively3、SO2And CO2H。
Term " oxo " refers to=O groups；
Term " alkyl hydroxy " or " hydroxy alkyl " refer to alkyl defined herein, wherein at least the one of the alkyl Individual hydrogen atom is substituted by OH groups.
Term " alkoxy " used in this application includes-O- (alkyl), wherein alkyl as defined above.
Term " halogenated alkoxy " refers to alkoxy defined herein, wherein at least one hydrogen of the alkoxy is former Son is substituted by halogen (being preferably fluorine or chlorine, more preferably fluorine).
Term " hydroxy alkoxy base " refers to alkoxy defined herein, wherein at least one hydrogen of the alkoxy is former Son is substituted by OH groups.
Term " aminoalkyl " used in this application refers to one or more nitrogen-atoms and one or more described The group of alkyl as defined above on nitrogen-atoms.
" aralkyl " or " aryl alkyl " refer to aryl-alkyl-, wherein aryl and alkyl be as defined in this Application.It is preferred that Aralkyl include low alkyl group.The non-limiting examples of suitable aralkyl include benzyl, 2- phenethyls and naphthyl methyl.Its Combined by alkyl with parent fraction.
" heteroaryl alkyl " refer to by moieties (defined above) be connected with parent nucleus it is defined herein miscellaneous Aryl moiety.The non-limiting examples of suitable heteroaryl include 2- pyridylmethyls, quinolyl methyl etc..
" cycloheteroalkylalkyl " refer to by moieties (defined above) be connected with parent nucleus it is defined herein miscellaneous Ring group part.The non-limiting examples of suitable cycloheteroalkylalkyl include piperidino methyl, piperizinylmethyl etc..
It should also be noted that having any carbon of unsaturated valence link in the context of the application, scheme, embodiment and table And hetero atom is assumed to have the hydrogen atom of enough numbers to meet valence link.
When any variable is (for example, aryl, heterocycle, R2Deng) occurred more than once in any component or in the formula When, its definition at each occurrence with it is each it is other occur when definition it is unrelated.
Term " the N- oxides formed by the N atomic components of the heteroaryl " refers to that the nitrogen-atoms that heteroaryl contains is formed N- oxides.The exemplary and non-limiting examples of the N- oxides have：
Statement " wherein described pyridine radicals can include the N- oxides formed by its N atomic component " refers to following formula：
Term " composition " used in this application is intended to include the product of the specified composition comprising specified amount, and directly or Person's spawn caused by the combination of the specified composition of specified amount indirectly.
Term " deuterium " used in this application represents the stable isotope of the hydrogen with odd number proton and neutron.
Term " halo " used in this application represents the substituent with least one halogen, the halogen be selected from fluorine, chlorine, Bromine and iodine.
Term " cyano group " used in this application represents the substituent with the carbon atom being connected by three keys with nitrogen-atoms.
Term " amino " used in this application represents the substituent containing at least one nitrogen-atoms.
Term " (amino) alkoxy " used in this application is represented with least one amino and at least one alkoxy Substituent.
Term " aryloxy " used in this application represents the substituent of Ar-O- forms, and wherein Ar is application-defined Aryl.
Term " benzyl epoxide " refers to benzyl-O- groups.
Term " aryl alkenyl " refers to aryl defined herein, and it passes through alkenyl and molecule defined herein Remainder is connected.
Term " cycloalkyl alkoxy-" refers to cycloalkyl defined herein, and it passes through alcoxyl defined herein The remainder connection of base and molecule.
Term " methylenedioxy " used in this application represents there is structural formula-O-CH2- O- functional group, it passes through Two chemical bonds are connected via oxygen with molecule.
" alkoxyalkyl " used in this application expression-(alkyl)-O- (alkyl), wherein each " alkyl " independently is The alkyl that face is defined.
Term " (alkoxyalkyl) amino " used in this application represents there is at least one alkoxy alkane as defined above The substituent of base and at least one amino as defined above.
Term " spiro cycloalkyl group " used in this application refers to that what is be connected in the way of loop coil with cycloalkyl (is free of hetero atom ) spiro-cyclic groups.The part that non-limiting examples are as follows：
Term " spiroheterocyclic alkyl " used in this application refers to that what is be connected in the way of loop coil with Heterocyclylalkyl (is free of miscellaneous original Son) spiro-cyclic groups.The part that non-limiting examples are as follows：
Term " miscellaneous spiroheterocyclic alkyl " used in this application refers to that what is be connected in the way of loop coil with Heterocyclylalkyl (contains for example O, N or S's is heteroatomic) spiro-cyclic groups.The part that non-limiting examples are as follows：
" aryl " is represented by removing 6-20 or 6- that a hydrogen atom is obtained from the single carbon atom of Parent Aromatic ring system The monovalent aromatic alkyl of 10 carbon atoms.Aryl includes bicyclic groups, and it is unsaturated that the bicyclic groups include with saturation, part Ring, or aromatic carbocyclic or heterocyclic fused aromatic ring.Exemplary aryl includes but is not limited to be derived from benzene, naphthalene, anthracene, connection The group of benzene, indenes, indane, 1,2- dihydronaphthalene, 1,2,3,4- tetralyls etc..Optionally independently substitution has one or many to aryl Individual substituent described herein.The illustrative example of aryl includes but is not limited to following part：
Deng.
Exemplary substituted aryl includes：
Deng.
Term " heteroaryl " used in this application refer to it is monocyclic, or fused polycycle aromatic heterocyclic radical (have be selected from The ring structure of the annular atom of carbon atom and nitrogen, oxygen and sulfur heteroatom), each ring group has 3-24 annular atom.The application makes Term " heteroaryl " also includes the monovalent aromatic group of 5-, 6- or 7- yuan of rings, and including thick with 5-10 atom Cyclization system (at least one ring is aromaticity), the fusion ring system contains at least one miscellaneous original for being independently selected from nitrogen, oxygen and sulphur Son.The example of heteroaryl includes but is not limited to pyridine radicals, imidazole radicals, imidazopyridyl, pyrimidine radicals, pyrazolyl, triazolyl, pyrrole Piperazine base, tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, oxazolyls, isothiazolyl, pyrrole radicals, quinolyl, isoquinoline Quinoline base, indyl, benzimidazolyl, benzofuranyl, cinnolines base, indazolyl, indolizine base, phthalazinyl, pyridazinyl, triazine radical, Isoindolyl, pteridyl, purine radicals, oxadiazolyls, triazolyl, thiadiazolyl group, thiadiazolyl group, furazanyl, benzofuraxan base, benzene Bithiophene base, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, phthalazinyl and furopyridyl.Spiral shell Loop section is also included within the range of this definition.Heteroaryl, which optionally replaces, one or more substituents described herein.5 Or 6 unit's heteroaryl may be selected from optionally substituted pyridine radicals, pyrimidine radicals, thiazolyl, imidazole radicals, oxazolyl, isoxazolyls, pyrazoles Base, pyriconyl and benzimidazolyl.
Illustratively and simultaneously without limitation, the heterocyclic radical and heteroaryl of carbon connection are connected as follows：In pyridine 2,3, 4th, 5 or 6 connections；3,4,5 or 6 connections in pyridazine；In pyrimidine 2,4,5 or 6 connections；In pyrazine 2,3,5 or 6 companies Connect；In furans, tetrahydrofuran, thiapyran, thiophene, pyrroles or nafoxidine 2,3,4 or 5 connections；Oxazoles, imidazoles or thiazole 2,4 or 5 connections；Isoxazoles, the 3 of pyrazoles or isothiazole, 4 or 5 connections；In 2 or 3 connections of aziridine；In nitrogen Azetidine 2,3 or 4 connections；In quinoline 2,3,4,5,6,7 or 8 connections；Or 1,3,4,5,6, the 7 of isoquinolin Or 8 connections.Other examples of the heterocyclic radical of carbon connection include pyridine -2- bases, pyridin-3-yl, pyridin-4-yl, pyridine -5- It is base, pyridine -6- bases, pyridazine -3- bases, pyridazine -4- bases, pyridazine -5- bases, pyridazine -6- bases, pyrimidine -2-base, pyrimidine-4-yl, phonetic Pyridine -5- bases, pyrimidine -6- bases, pyrazine -2- bases, pyrazine -3- bases, pyrazine -5- bases, pyrazine -6- bases, thiazol-2-yl, thiazole-4-yl Or thiazole -5- bases.
Illustratively and simultaneously without limitation, the heterocyclic radical and heteroaryl of nitrogen connection are connected as follows：In aziridine, azepine Cyclobutane, pyrroles, pyrrolidones, 2- pyrrolins, 3- pyrrolins, imidazoles, imidazolidine, 2- imidazolines, 3- imidazolines, pyrazoles, pyrrole Oxazoline, 2- pyrazolines, 3- pyrazolines, piperidines, piperazine, indoles, indoline, 1 connection of 1H- indazoles；In iso-indoles or different 2 connections of indoline；In 4 connections of morpholine；And in 9 connections of carbazole or B-carboline.Still more typically, nitrogen connects The heterocyclic radical connect includes aziridine -1- bases, azetidine -1- bases, pyrroles -1- bases, imidazoles -1- bases, pyrazol-1-yl and piperazine Pyridine -1- bases.
The illustrative examples of heteroaryl and the heteroaryl of substitution include but is not limited to following part：
Deng.
Term " bicyclic heteroaryl " refers to such structure, i.e. the atomic arrangement of this structure in two rings, the two Ring is fused together with least two public atoms of each ring, and at least one ring is heteroaryl ring.Bicyclic heteroaryl, bag Include containing 1,2,3 or 4 be independently selected from N, S or O heteroatomic 5-13 members or the non-limiting reality of 5-10 member bicyclic heteroaryls Under for example：
Deng.
The further example of bicyclic heteroaryl includes but is not limited to：
These bicyclic heteroaryls can be as to being substituted as defined herein.
Term " cycloalkyl " used in this application refers to saturation or fractional saturation monocyclic or fusion or loop coil Polycyclic carbocylic radical, each ring has 3-24 (C3-C24), 3-12 (C3-C12), 3-10 (C3-C10) or 3-6 (C3-C6) Annular atom.The non-limiting examples of " cycloalkyl " include but is not limited to following part：
Deng.
Term " Heterocyclylalkyl " used in this application refers to monocyclic or fusion or the polycyclic ring structure of loop coil, and it is There are saturation or fractional saturation and each ring 3-24 to be selected from C atoms and the heteroatomic annular atom of N, O and S.It is miscellaneous Cycloalkyl and the illustrative examples of the Heterocyclylalkyl of substitution include but is not limited to：
Deng.
Number range used in this application is intended to include continuous integer.For example, be expressed as the scope of " 0-4 " comprising 0,1, 2nd, 3 and 4.
Term " substitution " used in this application refers to that the group specified or part carry one or more suitable substitutions Base.
Term " unsubstituted " used in this application refers to that the group specified does not carry substituent.
Term " optionally substituted " used in this application refers to that the group specified is unsubstituted or one or more Substituent replaces.
When showing multifunctional part, pointed out with the tie point of core by line.For example, (cycloalkyl oxy) alkyl-refer to Alkyl is the tie point with core, and cycloalkyl is connected by epoxide with alkyl.
Statement " NACT agent " generally refers to treat, mitigate, alleviate or improve the reagent of the side effect of chemotherapeutics.It is this Reagent includes changing blood cell development and ripe reagent.The example of NACT agent includes but is not limited to Filgrastim And erythropoietin(EPO) (erythropoietin) (filgrastim).Other this NACT agent include suppressing and chemotherapy Those nauseous reagents of the administration correlation of agent, such as 5-HT3Acceptor inhibitor (for example, Dolasetron (dolansetron), Granisetron (granisetron) or Ondansetron (ondansetron)), wrap with or without dexamethasone (dexamethasone)。
Term " chemotherapeutics " and " anticancer " typically refer to handle, prevent, treat (cure), cure, mitigate, alleviating, changing Become, correct, improving, improving or influence malignant tumour and the reagent of their transfer.This reagent (also referred to as " anticancer ") Example includes but is not limited to metacortandracin (prednisone), fluorouracil (fluorouracil) (for example, 5 FU 5 fluorouracil (5- FU)), Anastrozole (anastrozole), Bicalutamide (bicalutamide), carboplatin (carboplatin), cis-platinum (cisplatin), Chlorambucil (chlorambucil), cis-platinum, carboplatin, Docetaxel (docetaxel), Doxorubicin (doxorubicin), Flutamide (flutamide), interferon-' alpha ' (interferon-alpha), Letrozole (letrozole), Leuprorelin (leuprolide), megestrol acetate (megestrol), mitomycin (mitomycin), oxaliplatin (oxaliplatin), taxol (paclitaxel), Primycin (plicamycin) (MithracinTM), TAM (tamoxifen), thiotepa (thiotepa), Hycamtin (topotecan), valrubicin (valrubicin), vincaleukoblastinum (vinvlastin), any combinations of vincristine (vincristine) and any aforementioned agents.In addition this is then described Reagent.
" nicotinamide phosphoribosyl transferase " (also referred to as NAMPT, NMPRT, NMPRTase or NAmPRTase) (state Border nomenclature：E.C.2.4.2.12 it is) from natural precursor niacinamide biosynthesis NADH (NAD) Important enzyme.
It must be noted that and work as in specification and appended in use, singulative " one (a) ", " one kind (an) " and " (the) " include plural referents, unless the context clearly dictates otherwise.
When as therapeutic agent in use, can be by nicotinamide phosphoribosyl transferase described herein (NAMPT) shape Into inhibitor be administered together with one or more physiologically acceptable excipient.Physiologically acceptable carrier or tax Shape agent is the preparation that compound is added to the administration for wherein with dissolved compound or otherwise promoting compound.
The formulation of the present invention can contain the mixture of one or more the compounds of this invention, and can include art technology Other material is used as drug excipient known to personnel.This drug excipient includes for example following：Can be by stabilization additives It is bound in delivery of agents solution (delivery agent solution).For some medicines, the presence of this additive promotees Enter the stability and dispersiveness of reagent in the solution.The concentration of stabilization additives can be about 0.1-5% (W/V), preferably from about 0.5% (W/V).The suitable but nonrestrictive example of stabilization additives include gum arabic, gelatin, methylcellulose, Polyethylene glycol, carboxylic acid and its salt, and polylysine.It is preferred that stabilization additives be gum arabic, gelatin and methylcellulose.
Acidulant (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, watery hydrochloric acid, malic acid, nitric acid, phosphoric acid, phosphoric acid,diluted, Sulfuric acid, tartaric acid)；Aerosol propellant (butane, dichlorodifluoro-methane, dichlorotetra-fluoroethane, iso-butane, propane, trichloro-monofluoro Methane)；Air displacer (carbon dioxide, nitrogen)；Alcohol denaturant (Denatonium Benzoate, methyl iso-butyl ketone (MIBK), eight acetic acid sucrose Ester)；Basifier (liquor ammoniae fortis, ammonium carbonate, diethanol amine, diisopropanolamine (DIPA), potassium hydroxide, sodium acid carbonate, Boratex, carbonic acid Sodium, sodium hydroxide, triethanolamine)；Anticaking agent (see glidant)；Defoamer (dimeticone, Simethicone)；It is antimicrobial anti- Rotten agent (benzalkonium chloride, Benza, benzethonium chloride, benzoic acid, benzylalcohol, butyl p-hydroxybenzoate, Cetylpyridinium Chloride, three The chlorine tert-butyl alcohol, chloreresol, cresols, dehydroactic acid, ethyl hydroxy benzoate, methyl p-hydroxybenzoate, Sodium Methyl Hydroxybenzoate (methylparaben sodium), phenol, benzyl carbinol, phenylmercuric acetate, phenylmercuric nitrate, Potassium Benzoate, potassium sorbate, to oxybenzene Propyl formate, Propyl Sodium p-Hydroxybenzoate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thyme Phenol)；Antioxidant (ascorbic acid, ascorbyl palmitate, Butylated Hydroxyanisole, Butylated Hydroxytoluene, hypophosphorous acid, monothioglycerol, Propylgallate, sodium sulfoxylate formaldehyde, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol figuration Agent)；Buffer (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metapbosphate, phosphoric acid Potassium dihydrogen, sodium acetate, sodium citrate, sodium lactate solution, disodium hydrogen phosphate, sodium dihydrogen phosphate)；Capsule lubricant is (see tablet With capsule lubricant)；Chelating agent (natrium adetate, ethylenediamine tetra-acetic acid and salt, edetic acid(EDTA))；Coating agent (carboxymethyl cellulose Plain sodium, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl Ylmethyl cellulose, HPMCP, methacrylic acid copolymer, methylcellulose, poly- second two Alcohol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, Brazil wax, microwax, zeins)； Colouring agent (caramel, red colouring agent, yellow colouring agent, black colouring agent or blend, iron oxide)；Complexing agent (ethylenediamine tetra-acetic acid and Salt (EDTA), edetic acid(EDTA), gentisic acid ethanolamide, oxyquinoline sulfate)；Drier (calcium chloride, calcium sulfate, silica)；Breast Change and/or solubilizer (Arabic gum, cholesterol, diethanol amine (auxiliary material), glycerin monostearate, lanolin alcohol, lecithin, Mono-and diglycerides, MEA (auxiliary material), oleic acid (auxiliary material), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 are stearic Acid esters, polyoxyethylene (35) castor oil, polyoxyethylene (40) rilanit special, polyoxyl 10 oleate ether, polyoxyethylene (20) ten Six alkyl-octadecyl ether, polyoxyethylene (40) monostearate, polysorbate20, polysorbate 40, polysorbate 60th, polysorbate80, propylene glycol diacetate, propylene glycol monostearate, lauryl sodium sulfate, odium stearate, dehydration mountain Pears alcohol monolaurate, sorbitan monooleate, sorbitan monopalmitate, Arlacel-60, Stearic acid, triethanolamine, emulsifying wax)；Filter aid (powdered cellulose, siliceous earth,purified)；Flavouring and spices (anethole, benzene first Aldehyde, ethyl vanillin, menthol, gaultherolin, monosodium glutamate, neroli oil, peppermint, peppermint oil, peppermint spirit, rose Oil, stronger rose water, thymol, tolu balsam tincture, vanilla, tincture of vanilla, vanillic aldehyde)；Glidant and/or anticaking agent (silicic acid Calcium, magnesium silicate, cataloid, talcum)；Humectant (glycerine, hexylene glycol, propane diols, sorbierite)；Plasticizer (castor-oil plant Oil, diacetylated monoglycerides, diethyl phthalate, glycerine, single- and di- acetylated monoglyceride, polyethylene glycol, Propane diols, triacetin, triethyl citrate)；Polymer (for example, cellulose acetate, alkylcellulose, hydroxy alkyl cellulose, Acrylic polymer and copolymer)；Solvent (acetone, alcohol, Diluted Alcohol, amylene hydrate, Ergol, butanol, four chlorinations Carbon, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerine, hexylene glycol, isopropanol, methanol, dichloromethane, methyl-isobutyl Ketone, mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propane diols, sesame oil, water for injection, sterilized water for injection, sterilizing punching Scouring water, purified water)；Sorbent (powdered cellulose, charcoal, siliceous earth,purified)；Carbon dioxide sorbent (barium hydroxide lime, alkali Lime)；Curing agent (rilanit special, cetostearyl alcohol, cetanol, cetyl esters wax, tristearin, paraffin, poly- second Alkene excipient, stearyl alcohol, emulsifying wax, Chinese wax, yellow wax)；Suspending and/or tackifier (Arabic gum, agar, alginic acid, single tristearin Sour aluminium, bentonite, purified bentonite, magma bentonite, carbomer 934 p, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carboxylic first Base sodium cellulosate 12, carrageenan, microcrystalline cellulose and sodium cellulose glycolate cellulose, dextrin, gelatin, guar gum, hydroxyl second Base cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, aluminium-magnesium silicate, methylcellulose, pectin, polyethylene glycol oxide, poly- second Enol, PVP, propylene glycol alginate, silica, cataloid, sodium alginate, bassora gum, xanthan gum)；Sweetener (aspartame, dextrates, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium benzosulphimide, saccharin sodium, mountain Pears alcohol, solution sorbierite, sucrose, sompressible sugar, the sugar of confection, syrup)；Tablet binder (Arabic gum, alginic acid, Sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methyl are fine Tie up element, methylcellulose, polyethylene glycol oxide, PVP, pregelatinized starch, syrup)；Tablet and/or capsule diluent (carbon Sour calcium, Bibasic Calcium Phosphate, tricalcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, the right side The sugared excipient of rotation, fructose, kaolin, lactose, mannitol, sorbierite, starch, pregelatinized starch, sucrose, sompressible sugar, candy The sugar of agent)；Tablet disintegrant (alginic acid, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, polacrilin potassium, shallow lake Powder glycolic sodium, starch, pregelatinized starch)；Tablet and/or capsule lubricant (calcium stearate, behenate, Magnesium stearate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, purifying stearic acid, talcum, hydrogenated vegetable Oil, zinc stearate)；Tonicity agent (dextrose, glycerine, mannitol, potassium chloride, sodium chloride)；Medium：Flavoring and/or sweetened (aromatic elixir, compound elixir of benzaldehyde agent, iso-alcoholic elixir, Peppermint Water, sorbitol solution, syrup, tolu balsam syrup)；Medium Thing：Oil (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral Oil, light mineral oil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persic oil, sesame oil, soybean oil, spiny dogfish Alkane)；Medium：Solid carrier (sugar ball)；Medium：Sterile (water for injection,bacteriostatic, biocidal property sodium chloride injection)；Increase Viscous (see suspending agent)；Waterproofing agent (water repelling agent) (cyclomethicone, dimeticone, Simethicone)；And Moistening and/or solubilizer (benzalkonium chloride, benzethonium chloride, Cetylpyridinium Chloride, docusate sodium, nonoxynol 9, nonoxynol 10, pungent benzene Polyalcohols 9, poloxamer, polyoxyethylene (35) castor oil, polyoxyethylene (40), rilanit special, polyoxyethylene (50) stearic acid Ester, polyoxyl 10 oleate ether, polyoxyethylene (20), cetearyl base ether, polyoxyethylene (40) stearate, poly- mountain Pears alcohol 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, lauryl sodium sulfate, mono laurate Isosorbide Dinitrate, Single oleic acid sorbitan alcohol ester, the sour Isosorbide Dinitrate of single palm fibre, sorbitan monostearate, tyloxapol (tyloxapol)).The list is not exclusive, on the contrary, be only can in the formulation of the present invention excipient classification that use and The representative of specific excipient.
The compound of the present invention can forming salt, the salt is also within the scope of the present invention.When referring to there is the formula in the application Compound when, it is thus understood that including being referred to its salt, unless otherwise specified.Term " salt " used in this application refers to and nothing Machine and/or the acid salt of organic acid formation, and the basic salt with the formation of inorganic and/or organic base.In addition, when with the formula Compound contain basic moiety (such as, but being not limited to, pyridine or imidazoles) and acidic moiety (such as, but being not limited to, carboxylic acid) When, amphion (" inner salt ") can be formed and included in term used in this application " salt ".It is preferred that medicinal (that is, it is nontoxic, it is raw It is acceptable in Neo-Confucianism) salt, but other salt are also useful.The salt of compound with the formula can be for example by with lower section Method is formed：Make in medium (medium that such as salt is precipitated wherein) or in water-bearing media compound with the formula with A certain amount of (such as equivalent) acid or alkali reaction, are then freezed.
Exemplary acid addition salts include acetate, ascorbate, benzoate, benzene sulfonate, disulfate, boric acid Salt, butyrate, citrate, camphor hydrochlorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid Salt, maleate, mesylate, naphthalene sulfonate, nitrate, oxalates, phosphate, propionate, salicylate, succinate, Sulfate, tartrate, rhodanate, toluene fulfonate (also referred to as toluene fulfonate (tosylates)) etc..In addition, generally The acid being considered as suitable for from the salt of basic drug compound formation pharmaceutically useful is for example discussed in the following documents：P.Stahl et al,Camille G.(eds.)Handbook of Pharmaceutical Salts.Properties,Selection and Use.(2002)Zurich:Wiley-VCH；S.Berge et al,Journal of Pharmaceutical Sciences(1977)66(1)1-19；P.Gould,International J.of Pharmaceutics(1986)33 201- 217；Anderson et al,The Practice of Medicinal Chemistry(1996),Academic Press, New York；With The Orange Book (Food＆Drug Administration, Washington, D.C., they On website).These disclosures are incorporated herein to be used as reference.
Exemplary basic salts include ammonium salt, alkali metal salt such as sodium salt, lithium salts and sylvite, alkali salt such as calcium salt and magnesium Salt, with organic base (for example, organic amine) such as dicyclohexylamine, tert-butylamine formation salt, and with amino acid such as arginine, lysine Deng the salt of formation.Can be by Basic nitrogen-containing groups reagent such as elementary alkyl halide (for example, methyl, ethyl and butyl chloride, first Base, ethyl and butyl bromide and methyl, ethyl and butyl iodide), dialkyl sulfate (for example, dimethyl suflfate, dithyl sulfate and Dibutyl sulfate), long chain halide is (for example, decyl, lauryl and stearyl chloride, decyl, lauryl and stearic bromide and the last of the ten Heavenly stems Base, lauryl and stearyl iodine), aralkyl halide (for example, benzyl and phenethyl bromide) and other reagents it is quaternized.
For the purpose of the present invention, all these acid salt and basic salt are intended to the pharmaceutical salts in the scope of the invention, and And all acid salt and basic salt are deemed to be equivalent to the free form of corresponding compound.
The medicinal ester of the compounds of this invention is also considered as the part of the present invention.The medicinal ester of the compounds of this invention includes It is following：(1) obtained carboxylate is esterified to hydroxyl, wherein the non-carbonyl moiety of the carboxylic moiety of the ester is selected from straight chain Or branched alkyl (for example, acetyl group, n-propyl, the tert-butyl group or normal-butyl), alkoxyalkyl (for example, methoxy), virtue Alkyl (for example, benzyl), aromatic yloxy yl alkyl (for example, phenoxymethyl), aryl (for example, be optionally substituted with for example, halogen, C1-4Alkyl or C1-4The phenyl of alkoxy or amino)；(2) sulphonic acid ester, such as alkyl sulphonyl or arylalkyl sulfonyl (for example, Mesyl)；(3) amino-acid ester (for example, L- valyls or L- isoleucyl-s)；(4) phosphonate ester, and (5) phosphate monoester, Di-phosphate ester or phosphotriester.Phosphate can be further by such as C1-20Alcohol or its reactive derivatives are esterified or by 2,3- bis- (C6-24) esterification of acyl group glycol.
The present invention also includes the prodrug and solvate of the compounds of this invention.About prodrug discussion referring to T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems(1987)14 of the A.C.S.Symposium Series,and in Bioreversible Carriers in Drug Design,(1987) Edward B.Roche,ed.,American Pharmaceutical Association and Pergamon Press.Art Language " prodrug " refers to conversion in the body into the compound of the compound or pharmaceutically acceptable salt thereof, hydrate or solvate of formula of the present invention (such as prodrug).This conversion can occur (such as by metabolism or chemical process) through various mechanism, for example, by blood Hydrolyzed in liquid.About its prodrug purposes discussion referring to T.Higuchi and W.Stella, " Pro-drugs as Novel Delivery Systems,"Vol.14 of the A.C.S.Symposium Series,and in Bioreversible Carriers in Drug Design,ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987。
If for example, the compound or pharmaceutically acceptable salt thereof of formula of the present invention, hydrate or solvate contain carboxylic-acid functional Group, then prodrug can be included replaces the ester that the hydrogen atom of acid groups is formed with for example following group：For example, (C1-C8) alkyl, (C2-C12) alkanoyl epoxide methyl, 1- (alkanoyl epoxide) ethyl with 4-9 carbon atom, with 5-10 carbon atom It is 1- methyl isophthalic acids-(alkanoyl epoxide)-ethyl, the alkoxy-carbonyl oxy methyl with 3-6 carbon atom, former with 4-7 carbon 1- (alkoxy-carbonyl oxy) ethyl, the 1- methyl isophthalic acids with 5-8 carbon atom-(alkoxy-carbonyl oxy) ethyl, the tool of son There are N- (alkoxy carbonyl) amino methyl of 3-9 carbon atom, 1- (N- (alkoxy carbonyl) ammonia with 4-10 carbon atom Base) ethyl, 3- phthalidyls, 4- crotonocyls lactone group, γ-butyryl lactone -4- bases, two-N, N- (C1-C2) alkyl amino (C2-C3) alkane Base (such as beta-dimethyl amino-ethyl), carbamoyl-(C1-C2) alkyl, the N, (C of N- bis-1-C2) alkyl-carbamoyl- (C1-C2) alkyl and piperidino (C2-C3) alkyl, pyrrolidino (C2-C3) alkyl or morpholino (C2-C3) alkyl etc..
Similarly, if the compound of formula of the present invention contains alcohol functional group, prodrug can use for example following group to replace The hydrogen atom for changing alcohol groups is formed：For example, (C1-C6) alkanoyl epoxide methyl, 1- ((C1-C6) alkanoyl epoxide) ethyl, 1- first Base -1- ((C1-C6) alkanoyl epoxide) ethyl, (C1-C6) alkoxy-carbonyl oxy methyl, N- (C1-C6) alkoxycarbonyl amino Methyl, succinyl group, (C1-C6) alkanoyl, alpha-amido (C1-C4) alkyl, aryl-acyl and α-aminoacyl or α-aminoacyl-α- Aminoacyl, wherein each α-aminoacyl is independently selected from naturally occurring l-amino acid, P (O) (OH)2、-P(O)(O(C1-C6) alkane Base)2Or glycosyl (removing the group that hydroxyl is obtained from the carbohydrate of hemiacetal form) etc..
If the compound of formula of the present invention is combined with amine functional group, the available for example following group of prodrug replaces amido The hydrogen atom of group is formed：For example, (wherein R and R' are each independently (C for R- carbonyls, RO- carbonyls, NRR'- carbonyls1-C10) alkane Base, (C3-C7) cycloalkyl, benzyl or R- carbonyls be natural α-aminoacyl or natural α-aminoacyl) ,-C (OH) C (O) OY1(its Middle Y1For H, (C1-C6) alkyl or benzyl) ,-C (OY2)Y3(wherein Y2For (C1-C4) alkyl and Y3For (C1-C6) alkyl, carboxyl (C1-C6) alkyl, amino (C1-C4) alkyl or single-N- (C1-C6) alkylaminoalkyl group or two-N, N- (C1-C6) alkyl amino alkane Base) ,-C (Y4)Y5(wherein Y4For H or methyl and Y5For list-N- (C1-C6) alkyl amino morpholino, singly-N- (C1-C6) alkyl Amino piperidine -1- bases or single-N- (C1-C6) alkylaminopyrolidine -1- bases or two-N, N- (C1-C6) alkyl amino morpholine Generation, two-N, N- (C1-C6) alkylaminopiperidine -1- bases or two-N, N- (C1-C6) alkylaminopyrolidine -1- bases) etc..
The compounds of one or more present invention can exist with nonsolvated forms and with medicinal solvent such as water, The solvation form of ethanol etc. is present；The invention is intended to including solvation form and nonsolvated forms." solvate " refers to The compound of the present invention and the physical association form (association) of one or more solvent molecules.This physical association shape Formula is related to different degrees of ion or covalent bonding, including hydrogen bond.In some cases, for example when one or more solvent molecules During with reference in the lattice of crystalline solid, solvate is separable." solvate " includes solution and separable molten Agent.The non-limiting examples of appropriate solvent compound include alcoholate, methylate etc.." hydrate " is that solvent molecule is H2O Solvate.
The compound of one or more present invention optionally converts solvate.The preparation of solvate is known 's.Thus, for example, M.Caira et al, J.Pharmaceutical Sci., 93 (3), 601-611 (2004) are described The solvate of antifungal agent Fluconazole is prepared in ethyl acetate and from water.Solvate, half solvate, hydrate etc. Similar preparation method be described in E.C.van Tonder et al, AAPS PharmSciTech., 5 (1), article 12 (2004)；And in A.L.Bingham et al, Chem.Commun., 603-604 (2001).Typical non-limiting method Be included in temperature higher than environment temperature by the compounds of this invention of desired amount be dissolved in desired solvent (organic solvent or water or its Mixture) in, solution is then cooled down with the speed for being sufficiently formed crystal, then crystal is separated through standard method.Analytical technology example As infrared spectrum is shown, there is solvent (or water) in the crystal as solvate (or hydrate).
The compound and its salt, solvate, ester and prodrug of the present invention can be with their tautomeric form (such as acyl Amine form or imino-ethers form) exist.All these tautomeric forms are intended to be included within the scope of the present invention, and constitute this hair Bright part.
The compound of the present invention can contain asymmetric or chiral centre, therefore the compound can be with different three-dimensional different Configuration formula is present.All stereoisomeric forms in any ratio and its mixture of compound with different formulas, including racemic mixture, structure Into the part of the present invention.In addition, the present invention includes all geometric isomers and position isomer.If for example, with difference The compound of formula is combined with double bond or condensed ring, then cis and trans and mixture are also contained in the scope of the present invention.
Can by physical chemical differences of the non-enantiomer mixture based on them by methods known in the art (for example Chromatography and/or fractional crystallization) and it is separated into their independent diastereoisomer.Enantiomter can be separated as follows：Pass through Make enantiomeric mixture and suitable optically-active compound (such as chiral auxiliary such as chiral alcohol or Mo Xier acyl chlorides (Mosher ' S acid chloride)) react and enantiomeric mixture is changed into non-enantiomer mixture, separate described non- Enantiomter, and single diastereoisomer is changed into and (is for example hydrolyzed into) corresponding pure enantiomter.In addition, There is the compound of different formulas can be atropisomer (such as substituted aryl-linking compound) for some, and constitute this hair Bright part.Enantiomter can also be used chiral HPLC column to separate.
Compound with different formulas can also exist with different tautomeric forms, and form of ownership is included in this In the range of invention.In addition, the compound of all keto-enols and imine-enamine forms is also contained in the scope of the present invention.
As position isomer (for example, pyridin-4-yl and pyridin-3-yl), the compounds of this invention (including describedization Salt, solvate and the ester of those and prodrug of the salt of compound, solvate, ester and prodrug) all stereoisomer (examples Such as, geometric isomer, optical isomer etc.), those that can for example exist due to the asymmetric carbon on different substituents are different Structure body, including enantiomeric form (also may be present even if asymmetric carbon is lacked), rotameric forms, atropisomer and non-right Isomeric form is reflected to fall within the scope of the present invention (if for example, the compound with different formulas includes double bond or condensed ring, then suitable Formula-and trans-forms and its mixture are covered within the scope of the present invention.In addition, for example, all keto-enols of compound and Asia Amine-ene amine form is comprising in the present invention.).Each stereoisomer of the compounds of this invention, for example, be substantially free of other different Structure body, or can for example be mixed into racemic compound or three-dimensional different with all other stereoisomer or other selections Structure body is mixed.The chiral centre of the present invention can have S or R configurations, be defined as recommended by IUPAC 1974.Term " salt ", " The use of solvate ", " ester ", " prodrug " etc. is intended to apply equally to the enantiomter of the compounds of this invention, three-dimensional different Structure body, rotational isomer, dynamic isomer, position isomer, the salt of racemic compound or prodrug, solvate, ester and Prodrug.
Present invention additionally comprises the compounds of this invention of isotope marks, it is identical with those that the application is enumerated, except with The lower fact：One or more atom by atomic mass or mass number and the atomic mass that is generally found in nature or The different atom of mass number is substituted.The example for the isotope that can be bound in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, The isotope of fluorine and chlorine, such as respectively H,3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl。
Some isotope marks with different formulas compound (for example, with3H and14Those of C flag) in compound And/or it is useful in substrate tissue measure of spread.It is tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotope is particularly preferred, because Their easily prepared and detections.In addition, can obtain some derive from compared with greater metabolic stability with higher isotope such as deuterium (that is, H) substitution Property (for example, Half-life in vivo or the dose requirements of reduction for improving) treatment advantage, and therefore can be in some cases It is preferred that.The compound with different formulas of isotope marks generally can be by following with following in scheme and/or in implementation Similar operation is operated disclosed in example, prepared by the reagent for replacing nonisotopic labels with the reagent of appropriate isotope marks.
The compound of the present invention and the salt of compound of the present invention, solvate, the polymorphic forms meaning of ester and prodrug Comprising in the present invention.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of optimised quantity is administered orally.
The nicotinamide phosphoribosyl transferase biosynthesis that the benefit of the present invention includes intravenous administration optimised quantity suppresses Agent.
The nicotinamide phosphoribosyl transferase biosynthesis that the benefit of the present invention includes Intraperitoneal medication optimised quantity suppresses Agent.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of administration optimised quantity in wall.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of intramuscular administration optimised quantity.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of subcutaneous administration optimised quantity.
The nicotinamide phosphoribosyl transferase biosynthesis that the benefit of the present invention includes intratumoral administration optimised quantity suppresses Agent.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of intrathecal drug delivery optimised quantity.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis suppression that optimised quantity is administered in Subdural space Agent.
The benefit of the present invention includes the nicotinamide phosphoribosyl transferase biosynthesis inhibitor of peri-ocular administration optimised quantity.
Based on these results, the present invention has important implications for the design of the new therapeutic strategy of patient, and the patient suffers from There are cancer (including leukaemia and solid tumor), inflammatory disease, osteoporosis, atherosclerosis；IBS and sheet Apply for other illnesss disclosed or well known by persons skilled in the art.
Embodiment
One aspect of the present invention is related to compound disclosed in the present application.
One aspect of the present invention is related to compound, its be or can be nicotinamide phosphoribosyl transferase formation Inhibitor.
The inhibitor that one aspect of the present invention is related to the formation of nicotinamide phosphoribosyl transferase is being prepared for controlling Purposes in the medicine treat, prevent, suppressed or eliminate tumour.
The inhibitor that one aspect of the present invention is related to the formation of nicotinamide phosphoribosyl transferase is being prepared for controlling Purposes in the medicine treat, prevent, suppressed or eliminate cancer.
The inhibitor that one aspect of the present invention is related to the formation of nicotinamide phosphoribosyl transferase is preparing medicine use Purposes in treatment, prevention, the medicine for suppressing or eliminating cancer, wherein the cancer is selected from leukaemia, lymthoma, ovary Cancer, breast cancer, uterine cancer, colon cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, CNS cancers, carcinoma of urinary bladder, cancer of pancreas and suddenly Strange gold disease.
Invention further describes one or more kinds of methods of synthesis the compounds of this invention.
Invention further describes one or more kinds of purposes of the compounds of this invention.
Such as it is used together invention further describes the compounds of this invention with adjuvant with TNF, GCSF or other chemotherapeutics One or more kinds of purposes.
Invention further describes one or more kinds of purposes of the pharmaceutical composition of the present invention.
One aspect of the present invention is related to is preparing use as the inhibitor of the formation of nicotinamide phosphoribosyl transferase Purposes in the medicine for the treatment of inflammatory disease.
One aspect of the present invention is related to is preparing use as the inhibitor of the formation of nicotinamide phosphoribosyl transferase Purposes in the medicine for the treatment of inflammatory disease such as IBS or inflammatory bowel disease.
One aspect of the present invention is related to is preparing use as the inhibitor of the formation of nicotinamide phosphoribosyl transferase Purposes in the medicine for the treatment of osteopathy such as osteoporosis.
One aspect of the present invention is related to is preparing use as the inhibitor of the formation of nicotinamide phosphoribosyl transferase Purposes in the medicine for the treatment of disease of cardiovascular system such as atherosclerosis.
One aspect of the present invention is related to is preparing use as the inhibitor of the formation of nicotinamide phosphoribosyl transferase In treatment by the purposes in the medicine of disease or illness caused by elevated NAMPT levels.
This disease or illness are to be selected from following one or more：Cancer, oophoroma, breast cancer, uterine cancer, knot Intestinal cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, carcinoma of urinary bladder, cancer of pancreas, leukaemia, lymthoma, Hodgkin's disease, virus sense Dye, human immunodeficiency virus, hepatitis viruse, herpesviral, herpe simplex, inflammatory disorder, IBS, inflammatory bowel disease, Rheumatoid arthritis, asthma, COPD, osteoarthritis, osteoporosis, dermatitis, atopic dermatitis, silver bits Disease, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, graft versus host disease(GVH disease), A Er It is Ci Haimo diseases, cerebrovas-cularaccident, atherosclerosis, diabetes, glomerulonephritis, metabolic syndrome, non-small cell lung cancer, small Cell lung cancer, Huppert's disease, leukaemia, lymthoma, squamous cell carcinoma, kidney, urethra and carcinoma of urinary bladder, head and neck cancer, brain and Central nervous system cancer (CNS).
The compounds of this invention can be used for treatment proliferative diseases, such as cancer, autoimmune disease, virus disease, fungi Disease, neurology/neurodegeneration obstacle, arthritis, inflammation, anti proliferative (for example, retinopathy), neuron, alopecia And cardiovascular disease.
More specifically, the compound can be used for treating various cancers, it is including but not limited to following：Cancer, including bladder Cancer, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including ED-SCLC, non-small cell lung cancer), head and neck cancer, the cancer of the esophagus, courage Capsule cancer, oophoroma, cancer of pancreas, stomach cancer, cervical carcinoma, thyroid cancer, prostate cancer and cutaneum carcinoma, including squamous cell carcinoma；Lymph The hematopoetic tumor of sample pedigree, including leukaemia, acute lymphatic leukemia, acute lymphoblastic leukemia, B- are thin Born of the same parents' lymthoma, T- cell lymphomas, Hodgkin lymphoma, NHL, hairy cell lymphoma, lymphoma mantle cell, Myeloma and Burkitt lymphoma；The hematopoetic tumor of myeloid lineage, including acute and chronic myelogenous leukemia, spinal cord development Bad syndrome and promyelocytic leukemia；The tumour of mesenchymal derivation, including fibrosarcoma and rhabdomyosarcoma；Maincenter and week Enclose the tumour of nervous system, including astrocytoma, nerve-cell tumor, glioma and schwann's cell tumor；With other tumours, Including melanoma, seminoma, teratocarcinoma, osteosarcoma, the purple neck knurl (xenoderoma pigmentosum) of exophytic color, Keratoacanthoma (keratoctanthoma), thyroid follicular cancer and Kaposi sarcoma.
The compounds of this invention can induce or suppress Apoptosis.
The compounds of this invention can also be used for cancer chemo-preventive.Chemoprophylaxis is defined as to start to be mutated thing by blocking Part, or deteriorated again by blocking the progress of the pre-malignant cells sustained damage or suppressing tumour, suppress infiltrating cancer The development of disease.
Another aspect of the present invention is the method for suppressing the NAMPT approach in animal, and methods described is included in need The compounds of this invention of survival dose is administered in the animal.
Another aspect of the present invention is the pharmaceutical preparation for including the compounds of this invention.
Another embodiment of the present invention includes the pharmaceutical preparation of the present invention, wherein the pharmaceutical preparation is delivering medicine to the mankind Cause the reduction of tumor load afterwards.
The another embodiment of the present invention is pharmaceutical preparation, and it also includes one or more kinds of antitumor agents, chemotherapeutics, or Person's NACT agent.
The pharmaceutical preparation of the present invention can also include the NACT agent of therapeutically effective amount.
The NACT agent can be change blood cell development and ripe medicine.The non-limiting examples of NACT agent For Filgrastim, Pegfilgrastim and erythropoietin(EPO).
The invention further relates to treat or prevent the obstacle of the undue growth velocity correlation with cell in mammal Method, it includes the pharmaceutical preparation of the invention that effective dose is administered to the mammal.The non-limiting examples of obstacle include Cancer or the transfer from malignant tumour.
Another aspect of the present invention is with cancer or the lactations of other obstacles related to abnormal division cell is moved The method for suppressing growth of tumour cell and division speed in thing, it includes the of the invention of effective dose is administered to the mammal Pharmaceutical preparation.
Another embodiment of the present invention is that tumour or the excessive life to Bone tumour are treated in the mammal of needs The method of ostalgia caused by long, it includes the pharmaceutical preparation of the invention that effective dose is administered to the mammal.
The another embodiment of the present invention is that the compound containing NAMPT- inhibitor is delivered medicine to the mammal of needs Method, it include to the mammal be administered the present invention pharmaceutical preparation.In one embodiment, the mammal For the mankind.
The another embodiment of the present invention is the method for preparing pharmaceutical preparation, and it is medicinal that it includes at least one present invention of mixing Compound and optional one or more kinds of pharmaceutical excipients or additive.
The invention further relates to synthesize the method for the compounds of this invention.
The compound of the present invention
The present invention relates to include one or more compounds and its pharmaceutical salts described herein, solvate, ester, prodrug With the pharmaceutical composition of isomers.The invention further relates to point for inhibitory enzyme nicotinamide phosphoribosyl transferase (NAMPT) Son and its pharmaceutical salts, solvate, ester, prodrug and isomers.
One aspect of the present invention provides compound, composition, kit and the removing toxic substances for the NAMPT approach in mammal Agent, the compound has Formulas I and its pharmaceutical salts, solvate, ester and isomers：
Wherein
Ar1For aryl, heteroaryl or Heterocyclylalkyl, wherein the hetero atom number of each heteroaryl and Heterocyclylalkyl be 1, 2 or 3, and the hetero atom is independently selected from N, S or O, the wherein each aryl, heteroaryl and Heterocyclylalkyl can independent quilts in addition Aryl, heteroaryl or Heterocyclylalkyl substitution are condensed with aryl, heteroaryl or Heterocyclylalkyl, still other wherein described aryl, Any one in heteroaryl and Heterocyclylalkyl is unsubstituted or is optionally independently substituted by one or more substituents, described to take Dai Ji may be the same or different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,- CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z、 Alkyl, alkenyl, alkynyl, alkoxy-,-aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)- C (O)-alkyl ,-N (R3)-C (O)-aryl ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-heterocycle Alkyl ,-aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl, condition be when two adjacent ring hetero atoms are different for S or It is asynchronously O；
X is straight or branched C1-C6Alkyl；
L is selected from NHC (O) NH, OC (O) NH, NHC (O) O, OCH2C(O)NH、C(O)NH、NHC(S)NH、OC(S)NH、NHC (S)O、OCH2C (S) NH or C (S) NH；
A is aryl, heteroaryl, Heterocyclylalkyl or C3To C8Cycloalkyl, wherein each aryl, heteroaryl, Heterocyclylalkyl With cycloalkyl be unsubstituted or by 1,2,3 or 4 substituents replace, the substituent may be the same or different and be independently selected from Deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, alkoxy-,- Aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-virtue Base ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl；
Q is C (O), S (O), S (O)2；
R3For H, alkyl or aryl alkyl-；
Z is 0,1 or 2；And
Or
(i)(a)R1Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched C1 To C4Hydroxy alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, Cycloalkyl-alkyl-, hydroxy alkyl-, alkoxyalkyl-, miscellaneous spiro cycloalkyl group and miscellaneous spiroheterocyclic alkyl, wherein described in above-mentioned part The hetero atom of heteroaryl and Heterocyclylalkyl is independently selected from one or more N, O and S, and condition is that two adjacent ring hetero atoms are different When be S or be asynchronously O, wherein R in addition1Can be unsubstituted or optionally independently by (i) one or more substituents Substitution, the substituent may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (ammonia Base) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、- CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxy alkane Base)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl Oxo) alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,- N(R3)-C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-it is miscellaneous Cycloalkyl ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed； And (b) R2Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched C1To C4Hydroxyl Alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl alkane Base-, hydroxy alkyl-, alkoxyalkyl-, miscellaneous spiro cycloalkyl group and miscellaneous spiroheterocyclic alkyl, wherein heteroaryl described in above-mentioned part and The hetero atom of Heterocyclylalkyl is independently selected from one or more N, O and S, condition be when two adjacent ring hetero atoms are different for S or It is asynchronously O, in addition wherein R2It can be unsubstituted or optionally independently replaced by (i) one or more substituents, institute Substituent is stated to may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alcoxyl Base-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed；
Or (ii) R1And R2C is formed together with the N that they are connected is shown in formula3-C8Heterocyclylalkyl, C3-C8Heterocycle alkene Base, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl, wherein each described miscellaneous Cycloalkyl, heterocycloalkenyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl optionally show them containing one or more remove in formula Hetero atom outside the N connected, the hetero atom is selected from N, S and O, and condition is that two adjacent ring hetero atoms are S when different Or be asynchronously O, the wherein each Heterocyclylalkyl, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, heterocycle alkene in addition Base, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl are unsubstituted or are optionally independently substituted by one or more substituents, described Substituent may be the same or different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alcoxyl Base-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl；
Condition is that the compound of formula I is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
Another aspect of the present invention provides the compound for the NAMPT approach in mammal, composition, kit and conciliate Toxic agent, the compound has Formulas I, wherein X, L, Q, Ar1With A as defined in Formulas I, and R1Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched C1To C4Hydroxy alkyl, aryl, heteroaryl, heterocycle alkane Base, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl-alkyl-, hydroxy alkyl-, alkoxy alkane Base-, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl, wherein the hetero atom of the heteroaryl and Heterocyclylalkyl described in above-mentioned part is independently selected From one or more N, O and S, condition is S when being two adjacent ring hetero atoms differences or is asynchronously O, in addition wherein R1Can To be unsubstituted or optionally independently be replaced by (i) one or more substituents, the substituent may be the same or different, and Be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkane Base) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, Hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2、 (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) alkyl-, aryloxy, Heterocyclylalkyl Epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-Heterocyclylalkyl ,-aryl and heteroaryl, or optionally Independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed；And
R2Selected from H, straight or branched C1To C7Alkyl, straight or branched C1To C7Alkoxy, straight or branched C1To C4Hydroxyl Base alkyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl, aryl alkyl-, heteroaryl alkyl-, hetercycloalkylalkyl-, cycloalkyl Alkyl-, hydroxy alkyl-, alkoxyalkyl-, miscellaneous spiro cycloalkyl group and miscellaneous spiroheterocyclic alkyl, wherein the heteroaryl described in above-mentioned part One or more N, O and S are independently selected from the hetero atom of Heterocyclylalkyl, condition is that two adjacent ring hetero atoms are S when different Or be asynchronously O, in addition wherein R2It can be unsubstituted or optionally independently replaced by (i) one or more substituents, The substituent may be the same or different, and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkane Epoxide-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、- OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxy alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) amino-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) Alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)- C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkyl, alkylenedioxy group (for example, methylene-dioxy) ,-heterocycle alkane Base ,-aryl and heteroaryl, or optionally independently with (ii) cycloalkyl ,-Heterocyclylalkyl ,-aryl or heteroaryl-condensed；
Condition is that the compound of formula I is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
Another aspect of the present invention provides the compound for the NAMPT approach in mammal, composition, kit and conciliate Toxic agent, the compound has Formulas I, wherein X, L, Q, Ar1With A as defined in Formulas I, and R1And R2With showing them in formula The N connected forms C together3-C8Heterocyclylalkyl, C3-C8Heterocycloalkenyl, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkane Base, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl, wherein each Heterocyclylalkyl, heterocycloalkenyl, spiroheterocyclic alkyl and miscellaneous spiral shell are miscellaneous Cycloalkyl optionally contains one or more hetero atoms in addition to the N that they are connected is shown in formula, the hetero atom choosing From N, S and O, condition is S when being two adjacent ring hetero atoms differences or is asynchronously O, in addition wherein each heterocycle alkane Base, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, heterocycloalkenyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic alkyl are not take It is generation or it is optional be independently substituted by one or more substituents, the substituent may be the same or different and be independently selected from deuterium, halogen Element, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl )2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, hydroxy alkyl-, (hydroxyl Alkyl) epoxide ,-alkoxy, carboxyl, (alkoxyalkyl)-, (heteroaryl epoxide) alkyl-,-NO2, (alkoxyalkyl) ammonia Base-,-alkyl amino, dialkyl amido, (Heterocyclylalkyl oxo) alkyl-, aryloxy, Heterocyclylalkyl epoxide-, amino carbonyl Base-,-CHO ,-C (O) alkyl ,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-aryl ,-S (O2) alkyl ,-S (O2)CF3,-cycloalkanes Base, alkylenedioxy group (for example, methylene-dioxy) ,-Heterocyclylalkyl ,-aryl and heteroaryl；
R3For H, alkyl or aryl alkyl, condition is that the compound is not 1- (pyridin-3-yl methyl) -3- (4- amino Sulfonvlphenyl) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines - 1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
In one embodiment, the present invention relates to compound of formula I and its pharmaceutical salts, solvate, ester or isomers.
In the compound of Formulas I, each several part and substituent are independent selections.
In where applicable, embodiments below is related to Formulas I.Moreover, aryl, heteroaryl, heterocycle in these embodiments Alkyl, cycloalkyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic moieties and their representative part can independently be unsubstituted Or as described above be optionally substituted or optionally condense.Be set forth below in the embodiment of Formulas I any one or Multiple one or more the other combination of embodiment that can be with Formulas I of person.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For aryl, with And z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For heteroaryl, And z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For heterocycle alkane Base, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For with aryl, Heteroaryl or the aryl of Heterocyclylalkyl fusion, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For with aryl, Heteroaryl or the heteroaryl of Heterocyclylalkyl fusion, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For with aryl, Heteroaryl or the Heterocyclylalkyl of Heterocyclylalkyl fusion, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For aryl, its It is substituted as shown in Formulas I, IA or IB, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For heteroaryl, It is substituted as shown in Formulas I, IA or IB, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1For heterocycle alkane Base, it is substituted as shown in Formulas I, IA or IB, and z, X, L, A, Q, R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and X is straight chained alkyl, And Ar1、z、L、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and X is branched alkyl, And Ar1、z、L、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and L is-N (H)-C (O)-N (H)-, and Ar1、z、X、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and Q is-S (O2)-, And Ar1、z、X、A、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R3For H, and Ar1、z、X、A、Q、R1And R2As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R3For alkyl, with And Ar1、z、X、A、Q、R1And R2As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R3For aryl alkane Base, and Ar1、z、X、A、Q、R1And R2As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and z is 0, and Ar1、X、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and z is 1, and Ar1、X、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, and z is 2, and Ar1、X、A、Q、R1、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, and Ar1、z、X、A、Q、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R2For H, and Ar1、z、X、A、Q、R2And R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2For H, with And Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For alkane Base, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Aryl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Cycloalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For alkane Epoxide, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For hydroxyl Base alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base epoxide, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Aryl alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Alkyl-alkyl-, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Cycloalkyl-alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For alkane Epoxide alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For spiral shell Heterocyclylalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For spiral shell Hetercycloalkylalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For alkane Base, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Aryl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Cycloalkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Alkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base epoxide, wherein aryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For virtue Base alkyl, wherein aryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Aryl alkyl, wherein heteroaryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Alkyl-alkyl-, wherein cycloalkyl is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be miscellaneous Cycloalkyl-alkyl, wherein Heterocyclylalkyl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For spiral shell Heterocyclylalkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For spiral shell Hetercycloalkylalkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heteroaryl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heterocyclylalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Cycloalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryloxy, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryl alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heteroaryl alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Cycloalkyl-alkyl-, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Hetercycloalkylalkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Spiroheterocyclic alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Spiroheterocyclic alkyl-alkyl, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Alkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heteroaryl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heterocyclylalkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Cycloalkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryloxy, wherein aryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Aryl alkyl, wherein aryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Heteroaryl alkyl, wherein heteroaryl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Cycloalkyl-alkyl-, wherein cycloalkyl is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Hetercycloalkylalkyl, wherein Heterocyclylalkyl are substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Spiroheterocyclic alkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For alkyl, R2For Spiroheterocyclic alkyl-alkyl, it is substituted or condensed as previously discussed, and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For two Suberyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Propyl group (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Butyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Amyl group (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For ring Phenyl-methyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For benzyl Base (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For furan Mutter base (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For furan Mutter ylmethyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For benzene Base (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For naphthalene Base (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For connection Phenyl methyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For connection Phenyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For first Phenyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For pyrrole Piperidinyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For not Substituted pyridylmethyl (replacing as described above or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For benzene Base ethyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For benzyl (such as It is upper described unsubstituted, substitution or fusion), R2For benzyl (unsubstituted, substitution or fusion as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For quinoline Quinoline base (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2Wei Evil Oxazolyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For Yin Oxazolyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For two Hydrogen benzo dioxaBase (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As define 's.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For pyrrole Oxazolyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For four Hydrogen naphthyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2To be different Quinolyl (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1For H, R2For oxygen Miscellaneous penta ring group (unsubstituted as described above, substitution or fusion), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form Heterocyclylalkyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form heterocycloalkenyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form fused bicyclic Heterocyclylalkyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form fused tricyclic heterocycles alkyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form spiroheterocyclic alkyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form miscellaneous spiroheterocyclic alkyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form piperidyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form piperazinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form morpholinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form azepine base (azapenyl) (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As determine Justice.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form azetidinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form oxazepine bicyclooctyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form azabicyclic heptyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form Er hydrogen benzoxazinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form indolinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form thiomorpholine base (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form the light dydrocarbon alkenyl of aza-tricycle 13 (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As define 's.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form azaspiro decyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form tetrahydrochysene phthalazinyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form azabicyclic octyl group (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form diazacyclo heptyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form decahydroquinolyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form diaza spiro undecyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, R1And R2Together with N Form tetrahydro isoquinolyl (unsubstituted or substituted as described above), and Ar1, z, X, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1、z、X、A、Q And R3As defined, and R1And R2It is identical or different, wherein the R1And R2Independently be it is unsubstituted or by one or Multiple substituent substitutions, the substituent is identical or different, and is independently selected from-C (O) NH2, alkyl ,-C (O) NH (alkyl) ,-C (O) N (alkyl)2, halogen, morpholinyl, alkoxyalkyl-, alkenyl, alkyl, CF3, OH, CN, phenyl, isocyano group ,-N (H) C (O) CH3, phenylethyl-,-C (O) CH3, phenoxy group ,-S (O2)CH3、-S(O2)CF3, pyrazinyl ,-OCHF2、OCF3、OCH2F、-C≡ CH、-CH═CH2, methylene-dioxy, ethylenedioxy, benzyl epoxide, piperidyl ,-C (O) O-CH3, phenoxy group, oxypiperazin Base, oxo-pyrrolidine ylmethyl-, NH2, NH (alkyl ,-N (alkyl)2, morpholinyl oxoethyl-, oxo pyrrolinyl methyl-, Azacycloheptyl, nitrobenzophenone-, cyclopropyl, hydroxymethyl-, (hydroxy alkyl) epoxide-, isopropyl, ethyl, methyl and phenyl Acrylic-.
One embodiment of the invention provides compound of formula I, and wherein each several part is independent selection, Ar1、z、X、A、Q And R3As defined, and R1And R2C is formed together with N3-C8Heterocyclylalkyl, C3-C8Heterocycloalkenyl, fused bicyclic heterocycle alkane Base, fused tricyclic heterocycles alkyl, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl, wherein each C3-C8Heterocyclylalkyl, C3-C8It is miscellaneous Cycloalkenyl group, fused bicyclic Heterocyclylalkyl, fused tricyclic heterocycles alkyl, spiroheterocyclic alkyl or miscellaneous spiroheterocyclic alkyl independently are and not taken Generation or with one or more substituents, the substituent may be the same or different and be independently selected from-C (O) NH2, alkyl ,-C (O) NH (alkyl) ,-C (O) N (alkyl)2, halogen, morpholinyl, alkoxyalkyl-, alkenyl, alkyl, CF3, it is OH, CN, phenyl, different Cyano group ,-N (H) C (O) CH3, phenylethyl-,-C (O) CH3, phenoxy group ,-S (O2)CH3、-S(O2)CF3, pyrazinyl ,-OCHF2、 OCF3、OCH2F、-C≡CH、-CH═CH2, methylene-dioxy, ethylenedioxy, benzyl epoxide, piperidyl ,-C (O) O-CH3, benzene Epoxide, oxopiperazinyl, oxo-pyrrolidine ylmethyl-, NH2, NH (alkyl ,-N (alkyl)2, morpholinyl oxoethyl-, oxo pyrrole Cough up quinoline ylmethyl-, azacycloheptyl, nitrobenzophenone-, cyclopropyl, hydroxymethyl-, (hydroxy alkyl) epoxide-, isopropyl, second Base, methyl and phenylpropenyl-.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For aryl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For heteroaryl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For spiroheterocyclic alkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For miscellaneous spiroheterocyclic alkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For aryl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For heteroaryl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For spiroheterocyclic alkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For miscellaneous spiroheterocyclic alkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, A is phenyl, R2For heteroaryl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, A is phenyl, R2For Heterocyclylalkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, A is phenyl, R2For spiroheterocyclic alkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For aryl, R1For H, A is phenyl, R2For miscellaneous spiroheterocyclic alkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For heteroaryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For miscellaneous spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For phenyl, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For phenyl, R1For H, A is phenyl, R2For heteroaryl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For phenyl, R1For H, A is phenyl, R2For Heterocyclylalkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For phenyl, R1For H, A is phenyl, R2For spiroheterocyclic alkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For phenyl, R1For H, A is phenyl, R2For miscellaneous spiroheterocyclic alkyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For heteroaryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For heteroaryl, R1For H, R2For miscellaneous spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For heteroaryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For miscellaneous spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For aryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For heteroaryl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For Heterocyclylalkyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For miscellaneous spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For pyrrole radicals, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For pyrrole radicals, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For pyridylmethyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For pyrrole radicals, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For piperidyl, R1For H, R2For pyrrole radicals, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For pyridylmethyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2It is phenyl for hydroxy alkyl, A, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For phenylalkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For cycloalkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For the ring group of oxa- penta, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For quinolyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2Wei oxazolyls, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For miscellaneous spiroheterocyclic alkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For tetralyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For dihydrobenzo dioxaBase, A is phenyl, and z, X, L, Q and R3As determine Justice.
One embodiment of the invention provides compound of formula I, wherein NR1R2For non-annularity, wherein each several part is independent Selection, Ar1For pyridine radicals, R1For H, R2For alkoxyalkyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For piperidyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For morpholinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For piperazinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azepine base, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azetidinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For oxazepine bicyclooctyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azabicyclic heptyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For Er hydrogen benzoxazinyls, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For indolinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For thiomorpholine base, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For the light dydrocarbon alkenyl of aza-tricycle 13, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azaspiro decyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azaspiro undecyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For tetrahydrochysene phthalazinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azabicyclic octyl group, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For diazacyclo heptyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For decahydroquinolyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For diaza spiro undecyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For tetrahydro isoquinolyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For piperidyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For morpholinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For piperazinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azepine base, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azetidinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For oxazepine bicyclooctyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azabicyclic heptyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For Er hydrogen benzoxazinyls, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For indolinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For thiomorpholine base, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For the light dydrocarbon alkenyl of aza-tricycle 13, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azaspiro decyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azaspiro undecyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For tetrahydrochysene phthalazinyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azabicyclic octyl group, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For diazacyclo heptyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For decahydroquinolyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For diaza spiro undecyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For tetrahydro isoquinolyl, and z, X, L, A, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For piperidyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For morpholinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For piperazinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azepine base, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azetidinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For oxazepine bicyclooctyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azabicyclic heptyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For Er hydrogen benzoxazinyls, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For indolinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For thiomorpholine base, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For the light dydrocarbon alkenyl of aza-tricycle 13, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azaspiro decyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azaspiro undecyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For tetrahydrochysene phthalazinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For azabicyclic octyl group, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For diazacyclo heptyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For decahydroquinolyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For diaza spiro undecyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For aryl, NR1R2For tetrahydro isoquinolyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For piperidyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For morpholinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For piperazinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azepine base, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azetidinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For oxazepine bicyclooctyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azabicyclic heptyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For Er hydrogen benzoxazinyls, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For indolinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For thiomorpholine base, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For the light dydrocarbon alkenyl of aza-tricycle 13, A is phenyl, and z, X, L, Q and R3As define 's.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azaspiro decyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azaspiro undecyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For tetrahydrochysene phthalazinyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For azabicyclic octyl group, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For diazacyclo heptyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For decahydroquinolyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For diaza spiro undecyl, A is phenyl, and z, X, L, Q and R3As defined.
One embodiment of the invention provides compound of formula I, wherein NR1R2For ring-type, wherein each several part is independent choosing Select, Ar1For heteroaryl, NR1R2For tetrahydro isoquinolyl, A is phenyl, and z, X, L, Q and R3As defined.
Another embodiment of the present invention provides the compound for the NAMPT approach in mammal, composition, kit And antidote, the compound has Formula II compound and its pharmaceutical salts, solvate, ester, prodrug and isomers：
Ar1-(CHR)n-L-Ar2-X-R1
II
Wherein
Ar1For aryl, heteroaryl or Heterocyclylalkyl, wherein the hetero atom number of each heteroaryl and Heterocyclylalkyl be 1, 2 or 3, and the hetero atom is independently selected from N, S or O, the wherein each aryl, heteroaryl and Heterocyclylalkyl can independent quilts in addition Aryl, heteroaryl or Heterocyclylalkyl substitution are condensed with aryl, heteroaryl or Heterocyclylalkyl, still other wherein described aryl, Any one in heteroaryl and Heterocyclylalkyl is unsubstituted or is optionally independently substituted by one or more substituents, described to take Dai Ji may be the same or different and be independently selected from deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,- CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z、 Alkyl, alkenyl, alkynyl, alkoxy-,-aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)- C (O)-alkyl ,-N (R3)-C (O)-aryl ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-heterocycle Alkyl ,-aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl, condition be when two adjacent ring hetero atoms are different for S or It is asynchronously O；
R is H, straight or branched C1-C6Alkyl or aryl alkyl；
N is 0,1,2,3 or 4；
L is selected from NHC (O) NH, OC (O) NH, NHC (O) O, OCH2C(O)NH、C(O)NH、NHC(S)NH、OC(S)NH、NHC (S)O、OCH2C (S) NH or C (S) NH, condition is that then n is 0 when L is C (O) NH；
Ar2For aryl, heteroaryl, Heterocyclylalkyl or C3To C8Cycloalkyl, wherein each aryl, heteroaryl, heterocycle alkane Base and cycloalkyl be unsubstituted or by 1,2,3 or 4 substituents replace, the substituent may be the same or different and be independently selected from Deuterium, halogen, cyano group, isocyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2,-C (O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl, alkenyl, alkynyl, alkoxy-,- Aryloxy-, (alkoxyalkyl) epoxide-, (alkoxyalkyl) amino-,-N (R3)-C (O)-alkyl ,-N (R3)-C (O)-virtue Base ,-N (R3)-C (O)-O- alkyl ,-N (R3)-C (O)-O- aryl ,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,-C (O)-aryl ,-S (O)-aryl and heteroaryl；
X is S, S (O), S (O)2, O or C (O)；
R1For cycloalkyl ,-CHzF3-z, aryl, Heterocyclylalkyl, heteroaryl, alkyl ,-alkenyl ,-alkynyl, (aryl) alkyl-, (heteroaryl) alkyl-or (Heterocyclylalkyl) alkyl-, (i) the wherein each cycloalkyl, aryl, Heterocyclylalkyl, heteroaryl and alkane Base be unsubstituted or by 1,2,3,4 or 5 substituents replace, the substituent may be the same or different and be independently selected from deuterium, halogen Element, cyano group, amino, aminoalkyl-, (amino) alkoxy-,-CONH2,-C (O) NH (alkyl) ,-C (O) N (alkyl)2、-C(O) NH (aryl) ,-C (O) N (aryl)2、-CHzF3-z、-OCHzF3-z, alkyl ,-alkenyl ,-alkynyl, alkoxy-, hydroxyl ,-alkyl hydroxyl Base, aryloxy-or (alkoxyalkyl) amino-,-cycloalkyl ,-Heterocyclylalkyl ,-aryl ,-S (O)2- alkyl ,-S (O)2- virtue Base ,-S (O)2-CF3,-C (O) N (alkyl)2,-C (O) alkyl ,-NH-C (O)-alkyl ,-NH-C (O)-aryl, methylene-dioxy and Heteroaryl, (ii) in addition wherein each the cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl can additional optional with independent selection Aryl, heteroaryl, Heterocyclylalkyl or Cycloalkylfused；
R3For H, alkyl or aryl alkyl-；
Z is 0,1 or 2；
Condition be the compound of formula I be not 3- { 1- [(4- methoxyphenyls) sulfonyl] piperidin-4-yl } -1- (pyridine - 3- ylmethyls) urea, or 1- (4- Phenoxyphenyls) -3- (pyridin-3-yl methyl) thiocarbamide.
In the compound of Formula II, each several part and substituent are independent selections.
In where applicable, embodiments below is related to Formula II.Moreover, aryl, heteroaryl, heterocycle in these embodiments Alkyl, cycloalkyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic moieties and their representative part can independently be unsubstituted Or as described above be optionally substituted or optionally condense.Be set forth below in the embodiment of Formula II any one or Multiple one or more the other combination of embodiment that can be with Formula II of person.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heterocycle Alkyl, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For with virtue The aryl of base, heteroaryl or Heterocyclylalkyl fusion, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For with virtue The heteroaryl of base, heteroaryl or Heterocyclylalkyl fusion, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For with virtue The Heterocyclylalkyl of base, heteroaryl or Heterocyclylalkyl fusion, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, it is substituted as shown in Formula II, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, it is substituted as shown in Formula II, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heterocycle Alkyl, it is substituted as shown in Formula II, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, and z, X, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, and z, X, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, and z, X, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For virtue Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, and z, X, L, n, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, and n is 1, and z, X, L, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, and z, Ar2、R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, Ar2For aryl, and z, X, L, n, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, and z, X, L, n, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, and z, X, L, n, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, Ar2For aryl, and z, X, L, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, n is 1, and z, X, L, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, n is 1, and z, X, L, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, and z, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, and z, R1And R3As institute Definition.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, and z, R1And R3As institute Definition.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, and z, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, and z, R1And R3As determine Justice.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, and z, R1And R3As determine Justice.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, and z, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, and z, R1And R3As determine Justice.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, and z, R1And R3As determine Justice.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, and z, R1And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, and z, R1And R3As define 's.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, and z, R1And R3As define 's.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, N is 1, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, N is 1, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For cycloalkyl, and z, X, L, n and R3Such as It is defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For cycloalkyl, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For cycloalkyl, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, N is 1, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, N is 1, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3 As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3 As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3 As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For aryl, and z, X, L, n and R3As institute Definition.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For aryl, and z, X, L, n And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For aryl, and z, X, L, n And R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, Ar2For heteroaryl, R1For aryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, N is 1, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, N is 1, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For heteroaryl, and z, X, L, n and R3Such as It is defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For heteroaryl, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For heteroaryl, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, Ar2For heteroaryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, and n is 1, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, Ar2For aryl, N is 1, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, Ar2For aryl, N is 1, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3Such as It is defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-S (O2)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3Such as It is defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For CF3, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-S (O)-, Ar2For aryl, R1For CF3, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3Such as It is defined.
One embodiment of the invention provides compound, and wherein each several part is independent selection, Ar1For heteroaryl, R is Straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For CF3, and z, X, L, n and R3 As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X be-C (O)-, Ar2For aryl, R1For CF3, and z, X, L, N and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is H, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For CF3, and z, X, L, n and R3As institute Definition.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is straight chained alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1For heteroaryl Base, R is branched alkyl, n be 1, L for-N (H)-C (O)-N (H)-, X is-O-, Ar2For aryl, R1For CF3, and z, X, L, n and R3As defined.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, Ar1Selected from pyrrole Piperidinyl, imidazopyridyl, pyrazolyl, quinolyl and thienopyridine base.These each parts can be unsubstituted or appoint Independently substitution has one or more groups for choosing, and the group may be the same or different, and be independently selected from-NH2,-N (alkyl)2, (alkane Epoxide alkyl) epoxide-and pyrazolyl.
One embodiment of the invention provides the compound of Formula II, and wherein each several part is independent selection, R1Selected from ring Amyl group, CF3, phenyl, naphthyl, pyrimidine radicals, oxazolyls, the alkenyl of 13 carbon of 8- oxatricyclos six and thienyl.These each parts Can be that unsubstituted or optional independently substitution has one or more groups, the group may be the same or different, and independent choosing From-C (O) NH2、-S(O2)CH3, F, Cl, Br, methylene-dioxy, CF3、OCF3, alkyl, alkoxy, pyrazolyl, C (O) CH3And benzene Epoxide.
Ar in Formula II1-(CHR)n- L- particularly preferably parts are following part：
Another aspect of the present invention provides the compound for the NAMPT approach in mammal, composition, kit and conciliate Toxic agent, the compound and its pharmaceutical salts, solvate, ester and isomers are derived from Formulas I and Formula II, and with formula III：
Wherein
Ar1For comprising 1, the heteroatomic 5-12 unit's heteroaryls that 2,3 or 4 are independently selected from N, S or O, wherein the heteroaryl Base is unsubstituted or by one or more RaSubstitution, the RaSelected from-NH2, oxo, halogen, haloalkyl ,-NH (CO) O- alkane Base ,-C (O) NH2With 3,4- dihydroxy -5- methyltetrahydrofuran bases；And wherein described heteroaryl can comprising it is one or more by The N- oxides that the N atomic components of the heteroaryl are formed, condition is when being S or be different when two adjacent ring hetero atoms are different For O；
Ar2For aryl or comprising 1, heteroatomic 5 or 6 unit's heteroaryls that 2,3 or 4 are independently selected from N, S or O；
R is H, straight or branched C1-C6Alkyl or aryl alkyl；
R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkyl, hydroxy alkyl ,-S (O)2Alkane Base ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl；Haloalkyl, cycloalkyl； Aryl；Heterocyclylalkyl；Or heteroaryl；
Wherein：
The each cycloalkyl, aryl or heteroaryl be unsubstituted or by 1,2,3,4 or 5 substituents replace, it is described Substituent is identical or different and is independently selected from following：
Deuterium, halogen, cyano group, alkyl, hydroxyl, hydroxy alkyl, hydroxy alkoxy base, cyanoalkyl, haloalkyl, alkenyl, alkynes Base, alkoxy, alkyl alkoxy, halogenated alkoxy, aryl alkenyl-, aryloxy, benzyl epoxide, oxo ,-(CH2)q- NRbRc、-(CH2)q-CONRbRc、-S(O)2- alkyl ,-S (O)2- aryl ,-S (O)2NH- alkyl ,-S (O)2N (alkyl)2、-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3,-C (O) alkyl ,-C (O) aryl ,-C (O) alkenyl aryl ,-C (O) O- alkyl ,-NH-C (O) alkyl ,-NH-C (O) aryl, methylene-dioxy ,-(CH2)qCycloalkyl, cycloalkyl alkoxy-, aryl, aryl alkyl-,- (CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl,
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, haloalkyl, alkyl halides One or more of epoxide, oxo, cyano group, alkyl, haloalkyl or alkoxy replace；And
Aryl optionally also with independent selection of each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, heteroaryl Base, Heterocyclylalkyl or the ring of Cycloalkylfused formation two or three cyclic groups, two rings or three cyclic groups can be by halogen, cyano group, alkane One or more of base or alkoxy replace；
R2For O or it is not present,
RbAnd RcIt is independently selected from H, alkyl, hydroxy alkyl, alkoxy, aryl, alkoxyalkyl ,-S (O)2Alkyl and cycloalkanes Base, or RbAnd Rc5 or 6 circle heterocycles alkyl are formed together with the nitrogen-atoms that can be connected with them, wherein the Heterocyclylalkyl can contain There are one or more additional heteroatoms selected from N, S or O；
N is 0 or 1；
Q is 0,1 or 2；
Condition is that the compound of formula I is not 1- (pyridin-3-yl methyl) -3- (4- aminosulfonvlphenyls) thiocarbamide, 3- [4- (morpholine -4- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamides or 3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-4-yl methyl) thiocarbamide.
In one embodiment, the present invention discloses formula III compound and its pharmaceutical salts, solvate, ester or isomers.
In the compound of formula III, each several part and substituent are independent selections.
In where applicable, embodiments below is related to formula III.Moreover, aryl in these embodiments, heteroaryl, miscellaneous Cycloalkyl, cycloalkyl, spiroheterocyclic alkyl and miscellaneous spiroheterocyclic moieties and their representative part can independently be and not take It is generation or as described above be optionally substituted or optionally condense.It is set forth below any one in the embodiment of formula III Individual or multiple one or more other combination of embodiment that can be with formula III.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar2For Aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar2For Phenyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar2Tool There is following formula：
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar1For Pyridine.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar1Tool There is following formula：
Wherein RaSelected from-NH2, oxo, halogen, haloalkyl ,-NH (CO) O- alkyl ,-C (O) NH2With 3,4- dihydroxy- 5- methyltetrahydrofuran bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar1Tool There is following formula：
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, and n is 1.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base and n are 1.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and Ar2For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and Ar2For phenyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and Ar2For phenyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and Ar2Tool There is following formula：
And Ar1For pyridine radicals.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, and R is H.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base and R are H.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, and n is 1 and R is H。
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl It is H with R.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, and n is 1, Ar2For Phenyl and R are H.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2It is H for phenyl and R.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For- NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkyl, hydroxy alkyl ,-S (O)2Alkyl ,-(CH2)qCycloalkanes Base ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For- NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For-NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For-NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For-NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For-NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For-NR3R4, wherein R3For H and R4For aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For halogen Substituted alkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For haloalkyl.
One embodiment of the invention provides compound, and wherein each several part is independent selection, Ar1For pyridine radicals, Ar2 For phenyl, and R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For haloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For unsubstituted or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted C3-C12- cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted C3-C12- cycloalkyl, wherein cycloalkyl are selected from cyclopropyl, pentamethylene, suberyl, azaspiro [4.5] last of the ten Heavenly stems Base, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and the ring of (1S, 2S, 3S, 5R) -2,6,6- trimethyls two [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted C3-C12- cycloalkyl, wherein cycloalkyl are selected from cyclopropyl, pentamethylene, suberyl, nitrogen Miscellaneous spiral shell [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2,6,6- The ring of trimethyl two [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted C3-C12- cycloalkyl, wherein cycloalkyl are selected from cyclopropyl, pentamethylene, suberyl, azepine Spiral shell [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2,6,6- three Methyl bicyclic [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted C3-C12- cycloalkyl, wherein cycloalkyl be selected from cyclopropyl, pentamethylene, Suberyl, azaspiro [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) the ring of -2,6,6- trimethyls two [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For unsubstituted or substituted C3-C12- cycloalkyl, wherein cycloalkyl are selected from cyclopropyl, pentamethylene, cycloheptyl Base, azaspiro [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2, The ring of 6,6- trimethyls two [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted C3-C12- cycloalkyl, wherein cycloalkyl are selected from cyclopropyl, ring Pentane, suberyl, azaspiro [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2,6,6- trimethyls two ring [3.1.1] heptyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For unsubstituted or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted C6-C10- aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted C6-C10- aryl, wherein the aryl is selected from phenyl, naphthyl, tetralyl and 1H- indenes -5- bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted C6-C10- aryl, wherein the aryl is selected from phenyl, naphthyl, tetralyl and 1H- Indenes -5- bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted C6-C10- aryl, wherein the aryl be selected from phenyl, naphthyl, tetralyl and 1H- indenes- 5- bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted C6-C10- aryl, wherein the aryl is selected from phenyl, naphthyl, tetrahydrochysene Naphthyl and 1H- indenes -5- bases.
One embodiment of the invention provides compound, and wherein each several part is independent selection, Ar1For pyridine radicals, n is 1, and R1For unsubstituted or substituted C6-C10- aryl, wherein the aryl is selected from phenyl, naphthyl, tetralyl and 1H- Indenes -5- bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted C6-C10- aryl, wherein the aryl is selected from phenyl, naphthalene Base, tetralyl and 1H- indenes -5- bases.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For aryl And R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted Heterocyclylalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not It is substitution or it is substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S.
One embodiment of the invention provides compound, and wherein each several part is independent selection, Ar2For phenyl, and R1 For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1,2 or 3 heteroatomic 5-12 members selected from N, O or S it is miscellaneous Cycloalkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkane that 2 or 3 are selected from N, O or S Base.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 that 2 or 3 are selected from N, O or S Circle heterocycles alkyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not It is substitution or it is substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S, wherein Heterocyclylalkyl is selected from Azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholine base, 2,8- diaza spiros [5.5] undecyl, 8- oxygen Miscellaneous -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa- -8- azaspiros [4.5] decane and decahydro Quinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S, its Middle Heterocyclylalkyl is selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholine base, 2,8- diaza spiros [5.5] Undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa- -8- azaspiros [4.5] decane and decahydroquinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkyl that 2 or 3 are selected from N, O or S, wherein miscellaneous Cycloalkyl is selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholine base, 2,8- diaza spiros [5.5] 11 Alkyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa- -8- azaspiro [4.5] last of the ten Heavenly stems Alkane and decahydroquinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1,2 or 3 heteroatomic 5-12 members selected from N, O or S it is miscellaneous Cycloalkyl, wherein Heterocyclylalkyl are selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl base, thiomorpholine, 2,8- phenodiazines Miscellaneous spiral shell [5.5] undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa-s -8- Azaspiro [4.5] decane and decahydroquinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 circle heterocycles alkane that 2 or 3 are selected from N, O or S Base, wherein Heterocyclylalkyl are selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholine base, 2,8- diaza spiros [5.5] undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa- -8- azepines Spiral shell [4.5] decane and decahydroquinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 that 2 or 3 are selected from N, O or S Circle heterocycles alkyl, wherein Heterocyclylalkyl are selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholine base, 2,8- Diaza spiro [5.5] undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxygen Miscellaneous -8- azaspiros [4.5] decane and decahydroquinolyl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not Replace or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For aryl, And R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For unsubstituted or substituted heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not It is substitution or it is substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S.
One embodiment of the invention provides compound, and wherein each several part is independent selection, Ar2For phenyl, and R1 For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1,2 or 3 heteroatomic 5-12 members selected from N, O and S it is miscellaneous Aryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 that 2 or 3 are selected from N, O and S Unit's heteroaryl.
One embodiment of the invention provides formula III compound, and wherein each several part is independently selection, and R1For not It is substitution or it is substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S, wherein heteroaryl is selected from 1,3, 4- oxadiazolyls, (1R) -3- oxo -3H- spiral shells [2- benzofuran -1,3'- pyrrolidinyls, 3,4- dihydro -2H-1,4- Ben Bing Evil Piperazine base, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxasBase, 1,2,3,4- Tetrahydroisoquinoli-s Quinoline base, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,2- oxazolyls, 8- oxatricyclos [7.4.0.02 ,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- naphthane -1- bases, phenoxthine base, 3- nitrogen Miscellaneous spiral shell [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), alkenyls of 5,7,9,11- five, (4aR, 8aS) - Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S, wherein Heteroaryl be selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shells [2- benzofuran -1,3'- pyrrolidinyls, 3,4- dihydros - 2H-1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxasBase, 1, 2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,2- oxazolyls, 8- oxygen Miscellaneous three rings [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- naphthanes -1- Base, phenoxthine base, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), 5,7,9,11- Five alkenyls, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar2For phenyl, And R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S, wherein heteroaryl Base is selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shells [2- benzofuran -1,3'- pyrrolidinyls, 3,4- dihydros -2H- 1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxasBase, 1,2,3, 4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,2- oxazolyls, 8- oxa-s three Ring [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- naphthane -1- bases, fen Sai Evil bases, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), 5,7,9,11- pentaenes Base, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1,2 or 3 heteroatomic 5-12 members selected from N, O and S it is miscellaneous Aryl, wherein heteroaryl be selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shells [2- benzofurans -1,3'- pyrrolidinyl, 3,4- dihydro -2H-1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxasBase, 1,2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,2- oxazoles Base, 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- tetrahydrochysenes Naphthalene -1- bases, phenoxthine base, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), 5,7, The alkenyls of 9,11- five, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 unit's heteroaryls that 2 or 3 are selected from N, O and S, Wherein heteroaryl is selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shells [2- benzofuran -1,3'- pyrrolidinyls, 3,4- Dihydro -2H-1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxas Base, 1,2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1,2- oxazolyls, 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- naphthanes - 1- bases, phenoxthine base, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), 5,7,9, The alkenyls of 11- five, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
One embodiment of the invention provides formula III compound, and wherein each several part is independent selection, Ar1For pyridine Base, n is 1, Ar2For phenyl, and R1For it is unsubstituted or substituted containing 1, the heteroatomic 5-12 that 2 or 3 are selected from N, O and S Unit's heteroaryl, wherein heteroaryl are selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shell [2- benzofuran -1,3'- pyrroles Alkyl, 3,4- dihydro -2H-1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- dihydro -2H-1,5- benzos DioxaBase, 1,2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyridine radicals, pyrimidine radicals, 1, 2- oxazolyls, 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7, 8- naphthane -1- bases, phenoxthine base, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), the alkenyls of 5,7,9,11- five, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
Another embodiment of the present invention provides formula III compound, wherein Ar1For pyridine radicals, n is 1, Ar2For phenyl, and institute Formula is stated for formula III A：
Wherein R1And RaAs defined in formula III, condition be the compound be not N- [4- (phenyl sulfonyl) phenyl]- N'- (3- pyridylmethyls) urea, N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamides or 4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
Another embodiment of the present invention is formula III compound and its pharmaceutical salts, wherein Ar2For phenyl, and Ar1HaveStructure, and the formula are formula III B
Wherein：
RaTo be one or more, and it may be selected from amino, oxo, halogen, halo (C1-C6) alkyl ,-NH (CO) O- (C1-C6) Alkyl and-C (O) NH2；And wherein described pyridine radicals can include the N- oxides formed by its N atomic component；
R1For-NR3R4, wherein R3For H, C1-C6- alkyl or-S (O)2(C1-C6) alkyl, and R4For (C1-C6) alkyl, hydroxyl Base (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl；
Halo (C1-C6) alkyl,
Cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl
Wherein：
The each cycloalkyl, aryl or heteroaryl be unsubstituted or by 1,2,3,4 or 5 substituents replace, it is described Substituent is identical or different and is independently selected from following：
Halogen, cyano group, (C1-C6) alkyl, hydroxyl, hydroxyl (C1-C6) alkyl, hydroxyl (C1-C6) alkoxy, halo (C1-C6) Alkyl, (C1-C6) alkoxy, (C1-C6) alkyl (C1-C6) alkoxy, halo (C1-C6) alkoxy, aryl (C2-C6) alkenyl-, Aryloxy, benzyl epoxide, oxo ,-(CH2)q-NRbRc、-(CH2)q-CONRbRc、-S(O)2-(C1-C6) alkyl ,-S (O)2NH- (C1-C6) alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3、-C(O)(C1-C6) alkyl ,-C (O) aryl ,-C (O) (C2-C6) alkene Base aryl ,-C (O) O- (C1-C6) alkyl ,-(CH2)qCycloalkyl, cycloalkyl (C1-C6) alkoxy-, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl,
Wherein each cycloalkyl, Heterocyclylalkyl, aryl or the sad halogen of heteroaryl, nitro, halo (C1-C6) alkyl, Halo (C1-C6) alkoxy, oxo, cyano group, (C1-C6) alkyl, halo (C1-C6) alkyl or (C1-C6) one in alkoxy or Multiple substitutions；
RbAnd RcIt is independently selected from H, (C1-C6) alkyl, hydroxyl (C1-C6) alkyl, (C1-C6) alkoxy, aryl, (C1-C6) alkane Epoxide (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl and (C3-C6) cycloalkyl, or RbAnd RcThe nitrogen that can be connected with them is former Son forms 5 or 6 circle heterocycles alkyl together, wherein the Heterocyclylalkyl can contain one or more extra miscellaneous originals selected from N, S or O Son,
Q is 0 or 1；And
Condition is that the compound is not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea,
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide, or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
One embodiment of the invention is formula III B compounds, wherein R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkyl, hydroxy alkyl ,-S (O)2Alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, virtue Base alkyl-,-(CH2)qHeteroaryl.
Another embodiment of the invention is formula III B compounds, wherein R1For NR3R4, wherein R3For H and R4For aryl.
Another embodiment of the invention is formula III B compounds, wherein R1For haloalkyl.
Another embodiment of the invention is formula III B compounds, wherein R1For unsubstituted or substituted C3-C12- ring Alkyl.
The still another embodiment of the present invention is formula III B compounds, wherein R1For unsubstituted or substituted C3- C12- cycloalkyl and cycloalkyl are selected from cyclopropyl, cyclopenta, suberyl, azaspiro [4.5] decyl, two rings [2.2.1] heptyl, two Ring [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2,6,6- trimethyls two ring [3.1.1] heptyl.
The yet another embodiment of the present invention is formula III B compounds, wherein R1For unsubstituted or substituted C6-C10- Aryl.
Another embodiment again of the present invention is formula III B compounds, wherein R1For unsubstituted or substituted C6-C10- Aryl and the aryl are selected from phenyl, naphthyl, tetralyl and 1H- indenes -5- bases.
Another embodiment of the invention is formula III B compounds, wherein R1For unsubstituted or substituted heterocycle alkane Base.
One embodiment of the invention is formula III B compounds, wherein R1Contain 1,2 or 3 to be unsubstituted or substituted The individual heteroatomic 5-12 circle heterocycles alkyl selected from N, O or S.
One embodiment of the invention is formula III B compounds, wherein R1Contain 1,2 or 3 to be unsubstituted or substituted The individual heteroatomic 5-12 circle heterocycles alkyl selected from N, O or S, and Heterocyclylalkyl is selected from azetidinyl, piperidyl, pyrrolidines Base, piperazinyl, thiomorpholine base, 2,8- diaza spiros [5.5] undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl, 1,4- Diazesuberanes base, 2- oxa- -8- azaspiros [4.5] decyls and decahydroquinolyl.
Another embodiment of the invention is formula III B compounds, wherein R1For unsubstituted or substituted heteroaryl.
Another embodiment of the invention is formula III B compounds, wherein R1Contain 1,2 to be unsubstituted or substituted Or 3 heteroatomic 5-12 unit's heteroaryls for being selected from N, O and S.
Another embodiment again of the present invention is formula III B compounds, wherein R1For it is unsubstituted or substituted containing 1, 2 or 3 heteroatomic 5-12 unit's heteroaryls selected from N, O and S, and heteroaryl is selected from 1,3,4- oxadiazolyls, (1R) -3- oxygen Generation -3H- spiral shells [2- benzofuran -1,3'- pyrrolidinyls, 3,4- dihydro -2H-1,4- benzoxazinyls, oxo -2,3- dihydros - 1H- indyls, 3,4- dihydro -2H-1,5- benzo dioxasBase, 1,2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, Thienyl, pyrazolyl base, pyridine radicals, pyrimidine radicals, 1,2- oxazolyls, 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkenyls of 3,5,10,12- six, 5- oxo -5,6,7,8- naphthane -1- bases, phenoxthine base, 3- azaspiros [5.5] hendecane Base, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), the alkenyls of 5,7,9,11- five, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetrahydrochysene -1,6- phthalazinyls.
The exemplary compounds of the present invention are as follows：
Following compounds are not the compounds of this invention, but are NAMPT inhibitor:
All articles and document that present specification is disclosed, are introduced to the application including patents and patent applicationss It is used as reference.
Embodiment
The present invention is further illustrated by the examples that follow, these embodiments should not be construed to the scope of the present invention or Person's purport is limited to the concrete operations described in embodiment.It would be recognized by those skilled in the art that initial substance can be changed and made The compound that the present invention covers is produced with other step, as described in the following Examples.In some cases, some reactive officials Can the protection of group can be necessary to realizing the conversion above some.The need for typically for this blocking group and connect To be obvious for the technical staff of organic synthesis field with the condition required for removing this group.Unless otherwise finger Go out, all reagents and solvent are normal business levels, and need not be further purified i.e. usable.
The following is exemplary, the nonrestrictive example of some embodiments of the invention.
Defined used in following proposal and other parts：
CDCl3Deuterated chloroform
δ chemical shifts (ppm)
DCM dichloromethane (dichloromethane or methylene chloride)
DIEA N, N- diisopropylethylamine
DMA DMAC N,N' dimethyl acetamides
DMAP N, N- lutidines -4- amine
DMF dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
DMSO-d6Deuterodimethylsulfoxide
EDCI N1- ((ethylimino) methylene)-N3, N3- dimethylpropane -1,3- diamine hydrochlorides
EtOAc ethyl acetate
EtOH ethanol
GF/F glass microfiber filters
1H NMR proton magnetic resonance (PMR)s
HOAc acetic acid
HATU 2- (3H- [1,2,3] triazol [4,5-b] pyridin-3-yl) -1,1,3,3- tetramethyl isourea Six
Fluorophosphate
HOBT 1H- benzos [d] [1,2,3] triazole -1- alcohol hydrates
HPLC high performance liquid chromatography
MHz megahertzs
KOAc potassium acetates
I-PrOH isopropanols
LC-MS liquid chromatography/mass spectrometries
(M+1) quality+1
M-CPBA metachloroperbenzoic acids
MeOH methanol
N2Nitrogen
NaHCO3Sodium acid carbonate
MgSO4Magnesium sulfate
SRB Sulforhodamine B colorimetric estimations
TEA triethylamines
THF tetrahydrofurans
TLC thin-layer chromatographys
It is prepared by compound
The compounds of this invention can be prepared by route known to the technical staff of a variety of organic synthesis fields.It is used as example Lift, the compounds of this invention can be used following methods together with synthetic method known to synthetic organic chemistry or its version to make It is standby, as it will be understood to a person of the art.It is preferred that method include but is not limited to those following methods.
The compounds of this invention urea-sulfonamide (IV) can be prepared by scheme 1 the step of general introduction.
Scheme 1
Intermediate II can be obtained as below：Temperature between -78 DEG C -200 DEG C, in atent solvent such as dichloromethane, benzene Or in toluene, by the processing of compound I phosgene, thiophosgene, carbonyl dimidazoles or other active groups.Intermediate V can be obtained as follows ：Temperature between -78 DEG C -200 DEG C, in atent solvent such as dichloromethane, benzene or toluene, by compound I chloromethanes Sour 4- nitrobenzene base ester processing.The compounds of this invention IV can be obtained as below：Temperature between -78 DEG C -200 DEG C, by compound III is handled in organic solvent with compound II or V.
The compounds of this invention urea-sulfone (IV) can be prepared by scheme 2 the step of general introduction.
Scheme 2
Intermediate II can be obtained as below：Temperature between -78 DEG C -200 DEG C, in atent solvent such as dichloromethane, benzene Or in toluene, by compound I phosgene, thiophosgene, carbonyl dimidazoles (or similar reagents) processing.The compounds of this invention IV can be such as It is lower to obtain：Temperature between -78 DEG C -200 DEG C, intermediate II is handled in organic solvent with III.
The compounds of this invention urea-sulfone IV can be prepared by scheme 2A the step of general introduction.
Scheme 2A
Intermediate VI can be obtained as below：Temperature between -78 DEG C -200 DEG C, in atent solvent such as dichloromethane and benzene In, handle compound III with compound V.With such as NaBH4, NaI or Na2S2O3Reagent in solvent such as water or THF ,- Temperature Treatment VI between 78 DEG C -200 DEG C, obtains intermediate VII.Compound IV can be obtained as below：Between -78 DEG C -200 DEG C Temperature, in atent solvent such as N, N- dialkylformamides, N, N- dialkyl acetamides or dichloromethane, in alkali (for example K2CO3、Cs2CO3、NR1R2R3, NaOR, KOR) in the presence of, with suitable transition-metal catalyst such as, but not limited to Pd (PPh3)4, acid chloride (II) or Cu (OAc)2Handle compound VII and VIII.
It will be appreciated by those skilled in the art that initial substance can be changed and additional step falls into this hair available for preparation Compound in bright scope (as following examples are shown).Unless otherwise indicated, all reagents and solvent are all standards Business level, and need not be further purified i.e. usable.
All articles and document that specification itself will be asked to disclose, are introduced to the application including patents and patent applicationss It is used as reference.
The preparation of representative urea-sulfonamide and urea-sulfone analog
Following examples illustrate the preparation of the urea-sulfonamide and urea-sulfone analog of representative substitution.
Embodiment 1
1- ((5- fluorine pyridin-3-yl) methyl) -3- (4- (piperidin-1-yl sulfonyl) phenyl) urea
Triphosgene (41mg, 0.137mmol) is dissolved in DCM (5mL), and is cooled in nitrogen atmosphere -10 DEG C.To In the solution of the cooling, be added dropwise 4- (piperidin-1-yl sulfonyl) aniline (100mg, 0.416mmol) and TEA (127mg, 1.25mmol) the mixture in DCM (5mL).The mixture is stirred 5 minutes at -10 DEG C, then warmed to room temperature, 1 is kept Hour.5- fluorine pyridin-3-yl methylamines (55mg, 0.50mmol) and TEA (127mg, 1.25mmol) are subsequently added into DCM (5mL) In solution.Reactant mixture is stirred at room temperature 16 hours.Mixture is diluted with DCM (25mL), with salt solution (2x 15mL) Washing, through MgSO4Dry, filter and be concentrated under reduced pressure.Thick material is purified into (using 5%MeOH/DCM elutions) through Biotage, Desired product is obtained, is white amorphous powder.
1H NMR(300MHz,CDCl3):δ9.23(s,1H),8.36-8.48(m,2H),7.50-7.68(m,5H),6.95 (t,1H),4.36(d,2H),2.75-2.90(m,4H),1.48-1.75(m,4H),1.38-1.42(m,2H)
LC-MS:393.04(M+1)。
Embodiment 2
N- (naphthalene -1- bases) -4- (3- (pyridin-3-yl methyl) urea groups) benzsulfamide
A:N- (naphthalene -1- bases) -4- nitrobenzene sulfonamides：
At 0 DEG C, into cooling solution of the naphthalene -1- amine (2000mg, 13.97mmol) in pyridine (45.0mL), add DMAP (171mg, 1.4mmol) and 4- nitrobenzophenone -1- sulfonic acid chlorides (3410mg, 15.4mmol) are molten in pyridine (15.0mL) Liquid.The mixture is stirred 15 minutes at 0 DEG C, 80 DEG C are then heated to, is kept for 16 hours.After cooling to room temperature, it will mix Thing is acidified with 2M HCl, is extracted with EtOAc (3x 50mL), with salt water washing several times, through MgSO4Dry, be then concentrated in vacuo. Thick material is purified into (using 5%EtOAc/ Hex) through Combiflash, title compound is obtained.
1H NMR(300MHz,CD3OD):δ7.21-7.38(m,6H),7.68-7.85(m,4H),8.15-8.20(m,2H)。
LC-MS:329.14(M+1)。
B:4- amino-N- (naphthalene -1- bases) benzsulfamide：
By N- (naphthalene -1- bases) -4- nitrobenzene sulfonamides (3.9g, 12mmol) and stannous chloride (II) dihydrate The mixture of (13.5g, 60mmol) backflow 2.5 hours in EtOAc (120mL).After cooling to room temperature, by mixture 2N NaOH (100mL) processing, and stir 1 hour, then filter, washed with EtOAc through diatomite.The filter vacuum of merging is dense Contracting.Thick material is purified into (using 40%EtOAc/ Hex) through Combiflash, title compound is obtained.
1H NMR(300MHz,CD3OD):δ6.45-6.51(m,2H),7.12-7.18(m,1H),7.25-7.38(m,5H), 7.65(d,1H),7.72-7.76(m,1H),7.91-7.98(m,1H)。
LC-MS:299.04(M+1)。
C:N- (naphthalene -1- bases) -4- (3- (pyridin-3-yl methyl) urea groups) benzsulfamide：
4- amino-N- (naphthalene -1- bases) benzsulfamides (1000mg, 3.35mmol) and chloro-carbonic acid 4- are stirred in a nitrogen atmosphere Mixture of the nitro phenyl ester (676mg, 3.35mmol) in DCM (35mL), and it is cooled to 0 DEG C, it is subsequently added into pyridine (1060mg,13.41mmol).After stirring 10 minutes, pyridine -3- methylamines (1087mg, 10.5mmol) are added, reaction is mixed Thing is stirred at room temperature 40 minutes.Then by mixture DCM-MeOH (100mL, 1:1) dilute, washed with water (5x 40mL), passed through MgSO4Dry, and be concentrated in vacuo.By residue through purification by flash chromatography (using 10%MeOH/DCM elutions), title is obtained Compound.
1H NMR(300MHz,DMSO-d6):δ4.21(d,2H),6.82-6.88(m,1H),7.10-7.16(m,1H), 7.32-7.55(m,8H),7.58-7.68(m,2H),7.85-7.89(m,1H),8.05-8.10(m,1H),8.40-8.46(m, 1H),8.52(s,1H),9.08(s,1H),10.08(s,1H)。
LC-MS:433.25(M+1)。
Embodiment 3
1- (4- (4,4- difluoropiperdin -1- bases sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea
A:4- (3- (pyridin-3-yl methyl) urea groups) phenyl -1- sulfonic acid chlorides：
Into ice cooling solution of the 4- isocyanatophenyl -1- sulfonic acid chlorides (6g, 27.6mmol) in THF (250mL), plus Enter pyridin-3-yl methylamine (2.79mL, 27.6mmol).Lasting 16 hours makes mixture slowly warm to room temperature.Filter out and give birth to Into precipitation.The volume of half is concentrated the filtrate to, is then handled with 200mL absolute ethers.Generated heavy is filtered out again Form sediment, mother liquor is handled with 200mL absolute ethers.The precipitation merged is collected, is title compound, it need not be further purified For in next step.
1H NMR(300MHz,CDCl3):δ 4.54 (s, 2H), 7.21 (width unimodal, 1H), 7.33 (d, 2H), 7.47 (d, 2H),8.08(dd,1H),8.55(dt,1H),8.50(m,2H),9.24(s,1H)。
B:1- (4- (4,4- difluoropiperdin -1- bases sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea：
To 4,4- difluoropiperdins hydrochloride (2g, 12.69mmol) and triethylamine (4.72mL, 33.8mmol) in dichloromethane In the ice cooling solution of (100mL), disposably add 4- (3- (pyridin-3-yl methyl) urea groups) phenyl -1- sulfonic acid chlorides (4.24g, 8.46mmol).The mixture is stirred 5 minutes at 0 DEG C, is then stirred at room temperature 16 hours.Mixture is dilute with dichloromethane Release, successively washed with saturated sodium bicarbonate aqueous solution, water and saturated sodium-chloride water solution.By organic extract through MgSO4Dry, Filter and be concentrated in vacuo.Thick material is purified into (using 10%MeOH/DCM elutions) through Biotage, title compound is obtained.
1H NMR(300MHz,DMSO-d6):δ2.05(m,4H),3.02(t,4H),4.33(d,2H),6.93(t,1H), 7.36(dd,1H),7.64(m,4H),7.71(m,1H),8.46(d,1H),8.53(s,1H),9.24(s,1H)；
LC-MS:410.40(M+1)
C18H20F2N4O3S analytically calculated value:C,52.67；H,4.91；N,13.65；F,9.26；S,7.81.Measured value： C,52.44；H,4.85；N,13.49；F,9.26；S,7.53.
Embodiment 4
1- (4- (4- morpholino piperidin-1-yls sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea
A:4- (1- (4- nitrophenylsulfonyls) piperidin-4-yl) morpholine：
Into ice cooling solution of the 4- nitrobenzophenone -1- sulfonic acid chlorides (4g, 18.05mmol) in DCM (50mL), 4- is added The solution of (piperidin-4-yl) morpholine (3.69g, 21.66mmol) and TEA (3.77mL, 27.1mmol) in DCM (920mL).Will The mixture is stirred 15 minutes at 0 DEG C, is then stirred at room temperature 16 hours.Mixture is diluted with DCM, with 1M NaOH, salt solution Washing, through Na2SO4Dry, be then concentrated in vacuo.Residue is handled with ether, generated precipitation is collected, obtains titled Compound.
1H NMR(300MHz,CDCl3):δ8.32-8.39(m,2H),7.89-7.97(m,2H),3.84(d,2H),3.60- 3.71(m,4H),2.15-2.50(m,6H),2.09-2.19(m,1H),1.85-1.92(m,2H),1.50-1.70(m,2H)
LC-MS:356.06(M+1)。
B:4- (4- morpholino piperidin-1-yls sulfonyl) aniline：
By 4- (1- (4- nitrophenylsulfonyls) piperidin-4-yl) morpholines (6.2g, 17.44mmol) and Raney Ni The mixture of (1.02g) in HOAc (50mL) is hydrogenated 16 hours in 50psi.Reactant mixture is filtered, filtrate is concentrated.Will be residual Excess is suspended in water (50mL), uses saturation NaHCO3The aqueous solution is neutralized.Precipitation is collected, and is dried under reduced pressure, obtains titled Compound.
1H NMR(300MHz,DMSO-d6):δ 7.21 (d, 2H), 6.61 (d, 2H), 6.03 (width unimodal, 2H) 3.45-3.65 (m,6H),2.30-2.41(m,4H),1.95-2.17(m,3H),1.69-1.79(m,2H),1.30-1.45(m,2H)
LC-MS:326.07(M+1)
C:1- (4- (4- morpholino piperidin-1-yls sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea：
Title compound is prepared according to embodiment 1, respectively with pyridin-3-yl methylamine and 4- (4- morpholino piperidin-1-yl sulphurs Acyl group) aniline replacement (5- fluorine pyridin-3-yl) methylamine and 4- (piperidin-1-yl sulfonyl) aniline.
1H NMR(300MHz,DMSO-d6):δ9.17(s,1H),8.51(d,1H),8.44(dd,1H),7.68(dd,1H), 7.52-7.69(m,4H),7.30-7.38(m,1H),6.89(t,1H),4.32(d,2H),3.45-3.59(m,6H),2.30- 2.41(m,4H),2.00-2.17(m,3H),1.69-1.79(m,2H),1.30-1.44(m,2H)
LC-MS:460.21(M+1)。
Embodiment 5
1- [(6- cyanopyridine -3- bases) methyl] -3- [4- (piperidines -1- sulfonyls) phenyl] urea
In a nitrogen atmosphere, triphosgene (41mg, 0.137mmol) is dissolved in DCM (5mL), and is cooled to -10 DEG C. Into the solution of the cooling, be added dropwise 4- (piperidin-1-yl sulfonyl) aniline (100mg, 0.416mmol) and TEA (127mg, 1.25mmol) the mixture in DCM (5mL).The mixture is stirred 5 minutes at -10 DEG C, then warmed to room temperature, 1 is kept Hour.Then 5- (amino methyl) pyridine -2- carbonitrile hydrochlorides (85mg, 0.50mmol) and TEA (2.52mmol) are added in DCM Solution in (5mL).Reactant mixture is stirred at room temperature 16 hours.Mixture is diluted with DCM (25mL), with salt solution (2x 15mL) wash, through MgSO4Dry, filter and be concentrated under reduced pressure.Thick material is purified through Biotage and (uses 5%MeOH/DCM Elution), desired product is obtained, is white amorphous powder (54mg, 32.5% yield).
1H NMR(300MHz,DMSO-d6):δ8.63(s,1H),7.79(m,2H),7.60(m,2H),7.48-7.54(m, 3H),6.10(m,1H),4.50(d,2H),2.93(m,4H),1.61(m,4H),1.41(m,2H)
LC-MS:400.01(M+1)。
Embodiment 6
5- ((3- (4- (piperidin-1-yl sulfonyl) phenyl) urea groups) methyl) pyridine-2-carboxamide
To 1- ((6- cyanopyridine -3- bases) methyl) -3- (4- (piperidin-1-yl sulfonyl) phenyl) urea (embodiment 5, 49mg, 0.123mmol) and solution of the potassium carbonate (33.9mg, 0.245mmol) in DMSO (5mL) in, add hydrogen peroxide (0.038ml,0.368mmol).Mixture is stirred at room temperature 16 hours, then diluted with EtOAc, with 1M NaOH and salt solution Continuous washing.By extract through Na2SO4Dry, filter, be concentrated in vacuo, then purified through Biotage and (use 10%MeOH/DCM Elution), obtain title compound.
1H NMR(300MHz,DMSO-d6):δ9.00(s,1H),8.42(m,2H),7.62(dd,1H),7.52-7.57(m, 3H),7.30-7.34(m,1H),6.34(t,1H),3.36-3.39(m,2H),2.74-2.82(m,4H),1.51(m,4H)1.32 (m,2H)
LC-MS:418.14(M+1)。
Embodiment 7
N- { 5- [({ [4- (piperidines -1- sulfonyls) phenyl] carbamoyl } amino) methyl] pyridine -2- bases } amino first Tert-butyl acrylate
In nitrogen atmosphere, triphosgene (122mg, 0.412mmol) is dissolved in DCM (5mL), and be cooled to -10 DEG C. Into the solution of the cooling, 4- (piperidin-1-yl sulfonyl) aniline (300mg, 1.248mmol) and TEA (2.52mmol) is added dropwise Mixture in DCM (10mL).The mixture is stirred 5 minutes at -10 DEG C, then warmed to room temperature, is kept for 1 hour.So Add afterwards 5- (amino methyl) pyridine -2- carbamates (293mg, 1.311mmol) and TEA (2.52mmol) in Solution in DCM (5mL).Reactant mixture is stirred at room temperature 16 hours.Mixture is diluted with DCM (25mL), salt solution is used (2x 15mL) is washed, through MgSO4Dry, filter and be concentrated under reduced pressure.Thick material is purified through Biotage and (uses 5%MeOH/ DCM is eluted), desired product is obtained, is white amorphous powder (200mg, 32.7% yield).
1H NMR(300MHz,DMSO-d6):δ8.19(s,1H),7.81(m,1H),7.74(s,1H),7.62(m,4H), 4.36(s,2H),2.93(t,4H),1.62(m,4H),1.52(s,9H),1.42(m,2H)
LC-MS:489.99(M+1)。
Embodiment 8
1- ((6- aminopyridine -3- bases) methyl) -3- (4- (piperidin-1-yl sulfonyl) phenyl) urea
By 5- ((3- (4- (piperidin-1-yl sulfonyl) phenyl) urea groups) methyl)-pyridine -2- carbamates (embodiment 7,87mg, 0.178mmol) is in 20ml 1:Solution in 1 TFA/DCM is stirred at room temperature 16 hours.It is molten removing After agent, residue is purified (using 10%MeOH (2M NH through Biotage3)/DCM is eluted), obtain title compound.
1H NMR(300MHz,DMSO-d6):δ8.00(s,1H),7.81(m,1H),7.7.40-7.50(m,4H),7.20- 7.35(dd,1H),6.38(d,1H).5.77(t,1H),4.18(d,2H),2.85(m,4H),1.53(m,4H),1.32(m,2H)
LC-MS:390.02(M+1)。
Embodiment 9
4- (N- (the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl)-N- (imidazo [1,2-a] pyridine -6- ylmethyls) benzene Formamide
A.N- (the chloro- 2- methoxyphenyls of 5-) -4- cvanobenzenesulfonamides：
To the chloro- 2- aminoanisoles of the 5- for being cooled to 0 DEG C (821mg, 5.21mmol, 1.05 equivalent) and DMAP (61mg, 0.496mmol, 0.1 equivalent) in solution in pyridine (15mL), be added dropwise 4- cyano-phenyl -1- sulfonic acid chlorides (1.0g, 4.96mmol, 1.0 equivalents) and solution in pyridine (5mL).Reactant mixture is heated overnight at 80 DEG C, is then removed in vacuum All volatile materials.The residue generated is dissolved in dichloromethane (20mL), successively with 1N hydrochloric acid (20mL), water (20mL) and saturated sodium-chloride (20mL) are washed, and then through anhydrous sodium sulfate drying, are filtered and are concentrated in vacuo.By what is generated Residue is ground twice with hexane (10mL), with ether (10mL) grinding once, is then dried in vacuo, is obtained N- (the chloro- 2- first of 5- Phenyl) -4- cvanobenzenesulfonamides (1.19g, 74%) are lavender solid, fraction solids need not be further purified Used in next step.
B.4- (N- (the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl) benzoic acid：
N- (the chloro- 2- methoxyphenyls of 5-) -4- cvanobenzenesulfonamides (0.387mmol, 125mg) are dissolved in 2- propyl alcohol In (8.0mL) and 1.8M potassium hydroxide aqueous solutions (6.5mL, 11.6mmol).By reactant mixture 75 DEG C heat 18 hours, so After be cooled to environment temperature, on the rotary evaporator remove 2- propyl alcohol.Aqueous phase is extracted with ethyl acetate (5mL), 2N is then used PH is adjusted to 2-3 by hydrochloric acid, and aqueous phase is extracted three times with ethyl acetate (10mL).The organic phase of merging is done through anhydrous sodium sulfate Dry, then filtering is concentrated in vacuo, obtains 4- (N- (the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl) benzoic acid, be white solid (123mg, 93%), it, which need not be further purified, to be used in next step.
C.4- (N- (the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl)-N- (imidazo [1,2-a] pyridine -6- ylmethyls) Benzamide：
To 4- (N- (the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl) benzoic acid (116mg, 0.340mmol, 1 equivalent) in In the solution of dry DMF (3mL), successively adding imidazo [1,2-a] pyridin-7-yl methylamine, (50mg, 0.340mmol, 1 work as Amount), BTA -1- bases-epoxide tripyrrole alkane Ji Phosphonium hexafluorophosphate (PyBOP, 194mg, 0.374mmol, 1.1 equivalent) With diisopropylethylamine (71 μ L, 0.408mmol, 1.2 equivalent).The yellow solution generated is small in environment temperature stirring 4.5 When, all volatile materials are removed in vacuum.Thick material (is washed through flash column chromatography using 2-8% ethanol/methylenes It is de-), title compound is obtained, is colorless oil, it is repeated with ether to grind, white solid (91mg, 57%) is obtained.
LCMS MH+=471.1
1H NMR(DMSO):δH 9.95(s,1H),9.24(t,1H),8.49(s,1H),8.00(2,2H),7.94(s, 1H), 7.82 (d, 2H), 7.53 (m, 2H), 7.19 (m, 3H), 6.94 (d, 1H), 4.47 (d, 2H) and 3.48 (s, 3H).
Embodiment 10
1- (4- (phenyl sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea
In a nitrogen atmosphere, solution of the triphosgene (84mg, 0.283mmol) in DCM (5.0mL) is cooled to -10 DEG C, Then 4- (phenyl sulfonyl) aniline (200mg, 0.857mmol) and TEA (260mg, 2.57mmol) is added dropwise in DCM (5.0mL) In solution.The mixture is stirred 5 minutes at -10 DEG C, then stirred 1 hour in environment temperature, in its backward mixture Add the solution of pyridin-3-yl methylamine (97mg, 0.90mmol) and TEA (260mg, 2.57mmol) in DCM (5.0mL).Will The mixture is stirred 16 hours in environment temperature, is then diluted, is washed with salt solution (2x 15mL), through MgSO with DCM (25mL)4 Dry.After filtration, filter vacuum is concentrated, purifies (using 5%MeOH/DCM elutions) through Biotage, obtain title compound Thing.
1H NMR(300MHz,DMSO-d6):δ4.29(d,2H),6.90(t,1H),7.26-7.35(m,1H),7.54- 7.70(m,6H),7.65-7.80(m,2H),7.81-7.90(m,2H),8.40-8.45(m,1H),8.49-8.55(m,1H), 9.21(s,1H).LC-MS:368.15(M+H)。
Embodiment 11
1- (pyridin-3-yl methyl) -3- (4- (2- (trifluoromethoxy) phenyl sulfonyl) phenyl) urea
A:4- (3- (pyridin-3-yl methyl) urea groups) phenyl -1- sulfonic acid chlorides：
4- isocyanatophenyl -1- sulfonic acid chlorides (6g, 27.6mmol) are absorbed in THF (250mL), 0 is subsequently cooled to DEG C, pyridin-3-yl methylamine (2.79mL, 27.6mmol) is added thereafter, is lasted 16 hours and is slowly warmed the mixture generated To environment temperature.Mixture is filtered, the initial volume of its half is concentrated the filtrate to, and with the anhydrous Et of 200mL2O processing.Again It is secondary to filter out precipitation, by filtrate with the anhydrous Et of 200mL2O processing.Vacuum filter collects generated precipitation, and it is without further Purifying can be used in next step.
1H NMR(300MHz,CDCl3):δ 4.54 (s, 2H), 7.21 (width unimodal, 1H), 7.33 (d, 2H), 7.47 (d, 2H),8.08(dd,1H),8.55(dt,1H),8.50(m,2H),9.24(s,1H)。
B:4- (3- (pyridin-3-yl methyl) urea groups) benzenesulfinic acid ammonium：
4- (3- (pyridin-3-yl methyl) urea groups) phenyl -1- sulfonic acid chlorides (3.99g, 12.25mmol) are added into sodium sulfite The solution of (6.18g, 49.0mmol) and sodium acid carbonate (6.17g, 73.5mmol) in water (175mL), by the solution generated Stirred 3 hours at 80 DEG C.Then mixture is concentrated under reduced pressure drying, the solid generated ground with hot DMF (100mL), mistake Filter out solid.Then removal of solvent under reduced pressure, the residue generated is ground with hot DCM (100mL), and vacuum filter is collected greyish white Color crystalline solid.Solid (is used 5 through SCX ion exchange column purifications:1CH3CN/NH4OH is eluted), obtain title compound.
1H NMR(300MHz,CDCl3):δ4.28(d,2H),7.35(m,6H),7.70(dt,1H),8.42(dd,1H), 8.51 (d, 1H), 9.23 (width unimodal, 1H) .LC-MS:292.01(M+1)
C:1- (pyridin-3-yl methyl) -3- (4- (2- (trifluoromethoxy) phenyl sulfonyl) phenyl) urea：
By 4- (3- (pyridin-3-yl methyl) urea groups) benzenesulfinic acid ammonium (30.8mg, 0.1mmol), 2- (trifluoromethyl) benzene Ylboronic acid (25.7mg, 0.125mmol), copper acetate (II) (22.7mg, 0.125mmol) and TEA (0.063mL, 0.45mmol) Mixture in DMSO (1.5mL) is heated 16 hours at 60 DEG C.Mixture is cooled to environment temperature, then distributed Between EtOAc and salt solution.Organic layer is separated, (MgSO is dried4), concentration purifies (100%EtOAc) through PTLC, obtains titled Compound.
1H NMR(300MHz,DMSO-d6):δ9.26(s,1H),8.50(d,1H),8.44-8.42(m,1H),8.17- 8.14(m,1H),7.84-7.78(m,1H),7.75-7.59(m,6H),7.52-7.49(m,1H),7.35-7.31(m,1H), 6.93(t,1H),4.30(d,2H)。LC-MS:452.09(M+1)
Embodiment 12
1- (3- aminobenzyls) -3- (4- (phenyl sulfonyl) phenyl) urea
A:3- ((3- (4- (phenyl sulfonyl) phenyl) urea groups) methyl) phenylcarbamate：
Title compound is prepared according to embodiment 1, and pyridine -3- is replaced with 3- (amino methyl) phenylcarbamate Base methylamine.
1H NMR(300MHz,CDCl3):δ7.82-7.89(m,2H),7.70-7.76(m,2H),7.42-7.58(m,4H), 7.38(d,2H),7.29(s,1H),7.10-7.16(m,2H),6.62-6.89(m,1H),6.65(s,1H),5.52(t,1H), 4.22(d,2H),1.47(s,9H)LC-MS:482.08(M+H)。
B:1- (3- aminobenzyls) -3- (4- (phenyl sulfonyl) phenyl) urea：
By 3- ((3- (4- (phenyl sulfonyl) phenyl) urea groups) methyl) Phenyl-carbamic acid tert-butyl ester (390mg, 0.810mmol) stirred 16 hours in environment temperature with solution of the TFA (5mL, 64.9mmol) in DCM (10mL).By mixture Concentration, is then distributed in DCM and saturation NaHCO3Between.Organic layer is washed with salt solution (2x 15mL), through Na2SO4Dry, mistake Filter and concentrate.Residue is purified into (using 10%MeOH/DCM elutions) through Biotage, title compound is obtained.
1H NMR(300MHz,DMSO-d6):δ9.21(s,1H),8.49-8.55(m,2H),8.40-8.45(m,2H), 7.81-7.90 (m, 5H), 6.90 (t, 1H), 6.69 (t, 1H), 6.40-6.50 (m, 3H), 5.41 (width unimodal, 2H), 4.14 (d, 2H)LC-MS:382.28(M+H)。
Embodiment 13
1- (4- ((4- chlorphenyls) sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea
A:4- (4- chlorophenyl sulfanyls) aniline：
By (4- chlorphenyls) (4- nitrobenzophenones) sulfane (1.71g, 6.44mmol) in 2:In 1MeOH/EtOAc (75mL) Solution is handled with platinum oxide (IV) (100mg), and the mixture generated then is placed in into hydrogen atmosphere (45psi) and holding 16 is small When.Mixture is filtered through GF/F filter paper, is eluted, is concentrated under reduced pressure with MeOH, obtain title compound, be yellow solid.
1H NMR(300MHz,CDCl3):δ7.32-7.27(m,2H),7.19-7.14(m,2H),7.05-7.01(m,2H), 6.70-6.65(m,2H),3.83(s,2H)。
B:1- (4- (4- chlorophenyl sulfanyls) phenyl) -3- (pyridin-3-yl methyl) urea：
Title compound is prepared according to embodiment 1, and 4- (phenyl sulfonyl) benzene is replaced with 4- (4- chlorophenyl sulfanyls) aniline Amine.
1H NMR(DMSO-d6):δ8.90(s,1H),8.51(d,1H),8.45-8.43(m,1H),7.71-7.67(m, 1H),7.51-7.46(m,2H),7.37-7.31(m,5H),7.11-7.06(m,2H),6.81(t,1H),4.30(d,2H)。
C.1- (4- ((4- chlorphenyls) sulfonyl) phenyl) -3- (pyridin-3-yl methyl) urea
By 1- (4- (4- chlorophenyl sulfanyls) phenyl) -3- (pyridin-3-yl methyl) ureas (50mg, 0.135mmol) in 10: 1DCM:Solution in MeOH (3.3mL) is handled with m-CPBA (2.0 equivalent), then stirs solution 16 hours in environment temperature. Then by mixture saturation NaHCO3With DCM dilutions, each layer is separated.By organic layer through MgSO4Dry, purify and (use through PTLC 6%MeOH/DCM is eluted), obtain title compound.
1H NMR(300MHz,DMSO-d6):δ9.24(s,1H),8.49(s,1H),8.43-8.42(m,1H),7.88(d, 2H),7.79(d,2H),7.68-7.58(m,5H),7.35-7.31(m,1H),6.92(t,1H),4.30(d,2H).LC-MS: 402.00(M+1)
Embodiment 14
1- ((6- (dimethylamino) pyridin-3-yl) methyl) -3- (4- (phenyl sulfonyl) phenyl) urea
A:6- (dimethylamino) pyridine -3- formonitrile HCNs：
In seal pipe, 6- chloropyridine -3- formonitrile HCNs (510mg, 3.68mmol) are absorbed in DMF (4mL) and dimethylamine In the solution of (4.0mL, 2.0M THF solution), DIEA (3.0mL, 17.18mmol) is then added.Heat the mixture to 140 DEG C, kept for 17 hours, then diluted, washed with salt solution (3x) with EtOAc, and dry (MgSO4).After filtering and concentration, Residue is purified into (100%MeOH/DCM/NH through Biotage SP13), title compound is obtained, is faint yellow solid.
1H NMR(300MHz,CDCl3):δ8.40(d,1H),7.60-7.56(m,1H),6.49-6.46(m,1H),3.15 (s,6H)。
B:5- (amino methyl)-N, N- lutidines -2- amine：
By 6- (dimethylamino) pyridine -3- formonitrile HCNs (506mg, 3.44mmol) in 2:1 2N NH3Solution in (75mL) Handled 16 hours in 40psi hydrogen atmospheres with Raney Ni.Then mixture is carefully filtered through diatomite and (noted:In order to keep away Exempt from fire, it is impossible to solid is dried), filtrate is concentrated and dried, (DCM/MeOH/NH is dried through Biotage SP13).Then will The cut Et of concentration2O is ground, and is obtained title compound, is white solid.
1H NMR(300MHz,DMSO-d6):δ7.97-7.94(m,1H),7.48-7.37(m,1H),6.57(d,1H), 3.95 (d, 2H), 3.55 (width unimodal, 2H), 2.96 (s, 6H).
C:1- ((6- (dimethylamino) pyridin-3-yl) methyl) -3- (4- (phenyl sulfonyl) phenyl) urea
Title compound is prepared according to embodiment 1, with 5- (amino methyl)-N, N- lutidines -2- amine replace pyridine - 3- base methylamines.
1H NMR(300MHz,DMSO-d6):δ9.05(s,1H),7.99(d,1H),7.90-7.86(m,2H),7.77(d, 2H),7.65-7.55(m,5H),7.44-7.41(m,1H),6.66(t,1H),6.57(d,1H),4.10(d,2H),2.96(s, 6H)。LC-MS:411.06(M+1)
Embodiment 15
1- (4- (4- Bromophenylsulfonyls) phenyl) -3- (pyridin-3-yl methyl) urea
A:(4- bromophenyls) (4- nitrobenzophenones) sulfane：
Solution of the 4- bromothiophenols (4.97g, 26.3mmol) in DMF (50mL) is cooled to 0 DEG C, K is then used2CO3 (4.3g, 31.1mmol) processing.After the addition is complete, last 15 minutes and solution is warmed to environment temperature, be subsequently added into 1- fluoro- 4- nitrobenzene (2.62mL, 24.70mmol).80 DEG C are heated the mixture to, is kept for 16 hours, is then poured onto on ice, uses EtOAc dilutes.Each layer is separated, by organic layer saturation NaHCO3Washed successively with salt solution (2x).By organic matter through MgSO4Dry, Filter and concentrate, obtain title compound, be yellow solid.
1H NMR(300MHz,DMSO-d6):δ8.18-8.13(m,2H),7.87-7.84(m,2H),7.53-7.41(m, 2H),7.31-7.27(m,2H)。
B:The bromo- 2- of 4- (4- nitrophenylsulfonyls) benzene：
(4- bromophenyls) (4- nitrobenzophenones) sulfane (3.942g, 12.71mmol) is cooled down in ice bath in CHCl3(40ml) In solution, then in batches with m-CPBA (2.2 equivalent) handle.Lasting 16 hours makes mixture slowly be warmed to environment temperature, Then mixture is filtered through GF/F filter paper, by filtrate with 1N NaOH and salt water washing.By organic matter through MgSO4Dry, filtering And it is condensed into crude solid.If desired, the solid can be ground with DCM, vacuum filter is collected, and obtains title compound Thing.
1H NMR(300MHz,DMSO-d6):δ8.42-8.36(m,4H),8.18-8.13(m,2H),7.87-7.84(m, 2H)。
C:4- (2- Bromophenylsulfonyls) aniline：
By the bromo- 4- of 1- (4- nitrophenylsulfonyls) benzene (1.57g, 4.59mmol) and stannous chloride (II) dihydrate The mixture of (4.35g, 22.94mmol) is heated 2 hours in EtOH (40mL) in 70 DEG C.Volatile materials is removed under reduced pressure, will Residue is absorbed in EtOAc (100mL) and 2N NaOH (40mL).Mixture is stirred vigorously 1 hour, then through diatomite Filtering.Organic layer is separated, through MgSO4Dry, purified through Biotage SP1, obtain title compound.
1H NMR(300MHz,DMSO-d6):δd 7.78-7.71(m,4H),7.52(d,2H),6.59(d,2H),6.22 (s,2H)。
D:1- (4- (4- Bromophenylsulfonyls) phenyl) -3- (pyridin-3-yl methyl) urea
Title compound is prepared according to embodiment 1, and 4- (phenyl sulfonyl) is replaced with 4- (4- Bromophenylsulfonyls) aniline Aniline.
1H NMR(300MHz,DMSO-d6):δ9.26(s,1H),8.50(d,1H),8.44-8.42(m,1H),7.83- 7.70(m,6H),7.69-7.65(m,1H),7.62-7.58(m,2H),7.35-7.31(m,1H),6.93(t,1H),4.30(d, 2H)。LC-MS:447.95(M+1)。
Embodiment 16
1- [(6- aminopyridine -3- bases) methyl] -3- [4- (benzenesulfonyl) phenyl] urea
A:5- ((3- (4- (phenyl sulfonyl) phenyl) urea groups) methyl) pyridine -2- carbamates：
The 30 minutes solution by 4- phenyl sulfonyls aniline (1.5g, 6.43mmol) in EtOAc (10mL) is lasted to be added dropwise To solution of the phosgene (6ml, 20% toluene) in toluene (5mL), then it is heated to reflux 5 hours.Volatile materials is removed under reduced pressure, Into residue add DCM (50mL), 5- (amino methyl) pyridine -2- carbamates (1.507g, 6.75mol) and DIEA(4mL).The mixture is stirred 16 hours in environment temperature, is then diluted, is washed with saturated sodium bicarbonate with DCM.Will Organic matter is through MgSO4Dry, concentration is filtered through Biotage SP1, obtains title compound.
1H NMR(300MHz,DMSO-d6):δ9.69(s,1H),9.15(s,1H),8.14(s,1H),7.87(dd,2H), 7.78(m,2H),7.70-7.73(m,1H),7.57-7.66(m,6H),6.81(t,1H),4.21(d,2H),1.44(s,9H)。
B:1- [(6- aminopyridine -3- bases) methyl] -3- [4- (benzenesulfonyl) phenyl] urea：
Title compound is prepared according to embodiment 3B, with 5- ((3- (4- (phenyl sulfonyl) phenyl) urea groups) methyl) pyrrole Pyridine -2- carbamates replace 3- ((3- (4- (phenyl sulfonyl) phenyl) urea groups) methyl) Phenyl-carbamic acid uncle Butyl ester.
1H NMR(300MHz,CDCl3):δ9.03(s,1H),7.86-7.89(m,2H),7.78-7.81(m,3H),7.58- 7.77(m,5H),7.27-7.31(dd,1H),6.63(t,1H),6.37(d,1H),5.81(s,2H),4.06(d,2H)
LC-MS:383.13(M+1)。
Embodiment 17
1- (pyridin-3-yl methyl) -3- (4- tosyls phenyl) urea
By (9,9- dimethyl -9H- xanthene -4,5- diyls) two (diphenylphosphines) (37.8mg, 0.065mmol), Cs2CO3 The palladium (0) (29.9mg, 0.033mmol) of (319mg, 0.980mmol), three (dibenzalacetone) two, 4- methyl sodium benzene sulphinates (140mg, 0.784mmol), 1- (4- bromophenyls) -3- (pyridin-3-yl methyl) urea (200mg, 0.653mg) and tetrabutyl iodate Mixture of the ammonium (290mg, 0.784mmol) in toluene (10mL) is heated 16 hours at 100 DEG C.Mixture is cooled to environment Temperature, adds DCM.Organic layer is used into water and salt water washing successively, through MgSO4Dry, concentration is dried through Biotage SP1, obtained To title compound.
1H NMR(300MHz,CDCl3):δ8.47(s,1H),8.44(d,1H),8.32(s,1H),7.69-7.74(m, 4H),7.63(d,1H),7.47-7.51(dd,2H),7.26-7.46(m,3H),6.12(s,1H),4.38(d,2H),2.37(s, 3H)LC-MS:382.15(M+1)。
Embodiment 18
N- (imidazo [1,2-a] pyridine -6- ylmethyls) -4- (phenyl sulfonyl) benzamide
A.4- (phenyl sulfonyl) benzonitrile：
4- fluorobenzonitriles (46.5mmol, 5.63g) and benzene sulfinic acid sodium salt (51.1mmol, 8.39g) are dissolved in DMSO In (35.8mL).Reactant mixture is heated 48 hours at 130 DEG C, environment temperature is subsequently cooled to, and be poured onto on ice.Take out The solid of precipitation is collected in filter, is washed with water, is then dried in vacuo, 4- (phenyl sulfonyl) benzonitrile (11.2g) is obtained, by one portion Divide to be further purified and can be used in next step.
B.4- phenylSulphon yl benzoic acid：
4- (phenyl sulfonyl) benzonitrile (4.11mmol, 1.0g) is dissolved in 2- propyl alcohol (88mL) and 1.0M potassium hydroxide is water-soluble In liquid (140mL).Reactant mixture is heated 18 hours at 75 DEG C, environment temperature is subsequently cooled to, removes on the rotary evaporator Remove 2- propyl alcohol.Aqueous phase is extracted with ethyl acetate (70mL), pH is then adjusted to 2-3 with 6N hydrochloric acid, aqueous phase is used into acetic acid again Ethyl ester (100mL) is extracted three times.The organic phase of merging is dried through anhydrous magnesium sulfate, is filtered, is then concentrated in vacuo, obtains 4- benzene Base sulfonyl benzoic acid, is white solid (1.01g), one part need not be further purified and be can be used in next step.
C.N- (imidazo [1,2-a] pyridine -6- ylmethyls) -4- (phenyl sulfonyl) benzamide：
At 0 DEG C, by oxalyl chloride (66.7 μ L, 0.763mmol) be added dropwise to 4- phenylSulphons yl benzoic acid (100mg, 0.381mmol) in the solution in dichloromethane (3.81mL).Reactant mixture is stirred 2 hours, volatilization is then removed in vacuum Property material.Rough 4- phenyl sulfonyl chlorobenzoyl chlorides are again dissolved in dichloromethane (3.8mL), imidazoles is then sequentially added And [1,2-a] pyridin-7-yl methylamine hydrochloride (77mg, 0.419mmol) and triethylamine (117 μ L, 0.839mmol).Will reaction Mixture is stirred 1 hour in environment temperature, then adds saturated sodium bicarbonate (3.8mL).Organic phase is separated, saturated sodium-chloride is used (3mL) is washed, and is dried through anhydrous magnesium sulfate, and be concentrated in vacuo.The residue generated (is used through flash column chromatography 5% ethanol/methylene is eluted) title compound is obtained, it is white solid (73mg, 49%).
LCMS MH+=391.9
1H NMR(MeOD):δH 8.29(s,1H),8.00(s,4H),7.93(d,2H),7.65-7.48(m,6H),7.27 (dd, 1H) and 4.50 (s, 2H).
Determine:
Determine embodiment 1
Biochemistry suppresses to determine
NAMPT protein purifications
The NAMPT of restructuring His marks is produced in Bacillus coli cells, is purified through Ni posts, and pass through through size exclusion post XTAL Biostructures are further purified.
NAMPT enzyme reactions
NAMPT enzyme reactions are in 96 hole V-type bottom plates in buffer A (50mM Hepes pH 7.5,50mM NaCl, 5mM MgCl2, and 1mM THP) middle progress.Compound titration individually dilution plate in by DMSO serial dilution compound enter OK, 100X liquid storages are prepared.By the buffer A (89 μ L) containing 33nM NAMPT albumen be added to containing control (for example, DMSO or Person's blank control) 1 μ L 100X compound plates., then will be in buffering by compound and enzymatic mixture in incubation at room temperature 15 minutes 10 μ L 10X substrates and confactor in agent A are added to experimental port, obtain following ultimate density：1 μM of NAM, 100 μM of 5- phosphorus Acid-D-ribose 1- pyrophosphoric acids (PRPP) and 2.5mM adenosine 5'-triphosphates (ATP).Make reaction room temperature carry out 30 minutes, then It is quenched by the 11 μ L solution for adding formic acid and L-cystathionine, obtains following ultimate density：1% formic acid and 10 μM of L-cystathionines. (or without) to the enzyme and CoFactor Mixture being quenched in advance by the way that NMN serial dilution is added, determine background and Signal intensity.
Quantify NMN
NAMPT reaction products (NMN) and internal contrast (L-cystathionine) are measured using based on mass spectrographic measure.Use Biocius Lifesciences operation, with RapidFire system detectios NMN and L-cystathionine.In brief, by NMN and L-cystathionine is loaded onto the graphitic carbon post in 0.1% formic acid, is eluted in 30% acetonitrile buffer, and be injected to Sciex 4000 In mass spectrum.By sample component electron spray ionization and detect cation.NMN Q1 (parent ion) and Q3 (fragment ions) Quality is respectively 334.2 and 123.2.The Q1 and Q3 of L-cystathionine are respectively 223.1 and 134.1.By the following method quantify and Analyze fragment.
% is determined using following methods to suppress.
First, by using the NMN signals divided by L-cystathionine signal in every hole, NMN signal normalizations to L-cystathionine are believed Number.The signal in background hole is averaged and subtracted from breadboard.Then the cell handled through compound is determined by using following formula % suppress.
% suppresses=100-100*x/y
Wherein x represents that the average signal and y in the hole handled through compound represent the average signal through the DMSO holes handled.
IC50 is determined using Excel and following formula.
IC50=10^ (LOG10 (X)+(((%s of the 50- in compound concentration 1 suppresses)/(XX-YY) * (LOG10 (X)- LOG10(Y))))
Wherein X represents compound concentration 1, and Y represents compound concentration 2, and XX represents the % suppressions at compound concentration 1 (X) System, and YY represent that the % at compound concentration 2 (Y) suppresses.
The IC50 values of the NAMPT- inhibitor compounds of the present invention are less than 10 μM, more preferably less than preferably shorter than 1 μM, 0.1 μ M, most preferably less than 0.01 μM.The result of compound is provided in table 3 below.
Determine embodiment 2
Cell in vitro proliferation assay
Adding and be not added with 180 μ L culture mediums (10% of β-nicotinamide mononucleotide (NMN) or niacinamide (NAM) FBS, 1%Pen/Strep Amphotecricin B, RPMI-5 1640) in, by A2780 cells with 1x 103Individual cells/well It is seeded in 96 orifice plates.In 37 DEG C and 5%CO2After overnight incubation, in individually dilution plate, pass through the serial dilution in DMSO Compound carries out compound titration, prepares 1000X liquid storages.Then compound is further diluted to 10X in the medium final The 20 each dilutions of μ L then, are added to plate hole, obtain 200 μ L by concentration together with control (for example, DMSO and blank control) Final volume.Final DMSO concentration in every hole is 0.1%.Then by plate in 5%CO2In couveuse 72 are incubated in 37 DEG C Hour.Then the number of survivaling cell is determined using Sulforhodamine B (sulforhodamine B, SRB).By cell at 4 DEG C 1 hour is fixed, the addition trichloroacetic acids of 50 μ L 30% (TCA) obtain 6%TCA ultimate density.By plate H2O is washed four times, And dry at least 1 hour, then, 100 μ L solution of the 4%SRB in 1% acetic acid are added to per hole and in incubation at room temperature at least 30 minutes.Then plate is washed three times with 1% acetic acid, dried, and with 100 μ L 10mM Tris- alkaline solution treatments.Then micro- With 570nm absorptance read plate in plate reader (microplate reader).Only the back of the body is produced on single plate with culture medium Scape.
Determine the method that % suppresses
First, the signal of background board is averaged, then subtracted background from breadboard.Then determined by using following formula The % of the cell handled through compound suppresses：
% suppresses=100-100*x/y
Wherein x represents that the average signal and y of the cell handled through compound represent being averaged through the DMSO cells handled Signal.
Formula for determining IC50 values：
IC50=10^ (LOG10 (X)+(((%s of the 50- in compound concentration 1 suppresses)/(XX-YY) * (LOG10 (X)- LOG10(Y))))
Wherein X represents compound concentration 1, and Y represents compound concentration 2, and XX represents the % suppressions at compound concentration 1 (X) System, and YY represent that the % at compound concentration 2 (Y) suppresses.
The specificity of cytotoxicity
NAMPT suppression can be reversed by adding NAM or NMN.The specificity of compound is determined by cell survival Determined in the presence of compound and NAM or NMN.Percentage is determined using method presented above to suppress.
Preferably shorter than 1 μM of the IC50 values of the NAMPT- inhibitor compounds of the present invention, more preferably less than 0.1 μM, most preferably Less than 0.01 μM.Most preferably compound of the invention is the compound that enzyme IC50- values and A2780IC50- values are below 10 μM, excellent Both are less than 1 μM of compound for choosing, and more preferably both of which is less than 0.1 μM of compound, and most preferably both of which is less than 0.01 μM Compound.The result of compound is provided in table 3 below.
Table 3
Xenograft is studied:
By C.B-17-Igh-1b-PrkdcscidMouse (female) uses 5X10 in left rib6A2780 cells (NCI) are subcutaneously noted Penetrate.When tumor size reaches 100-200mm after 10-12 days3When, mouse is divided at random to the treatment group of every group of 8 mouse (bag Include vehicle control group and reference standard group) in.Compound is prepared 60:30:10PEG-400:D5W:In ethanol, and with 10ml/kg dose volume is two times a day administered orally, and continues 5 or 10 days.Dosage for effect is selected from MTD, and (highest is resistance to By dosage) research.Every other day, mouse is weighed and uses vernier caliper measurement tumour.According to formula (length x width2Count)/2 Calculate gross tumor volume.All animal work are by Institutional Animal Care and Use Committee of Biological Resource Centre, Singapore approvals.
As a result：
Following compounds generate tumor regression (tumor regression)：
1- (4- { 8- oxa- -3- azabicyclics [3.2.1] octane -3- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) Urea；And
1- (pyridin-3-yl methyl) -3- (4- { [2- (trifluoromethoxy) phenyl] sulfonyl } phenyl) urea.
Following compounds generate tumor stasis (tumor stasis)：
3- { 4- [(the chloro- 2- methoxyl groups -5- aminomethyl phenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(4- fluorophenyls) sulfonyl] phenyl } -3- { imidazo [1,2-a] pyridine -6- ylmethyls } urea；
3- [4- (benzenesulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；And
1- [(6- aminopyridine -3- bases) methyl] -3- [4- (benzenesulfonyl) phenyl] urea.
Following compounds delays tumour growth (tumor growth)：
1- { 4- [4- (morpholine -4- bases) piperidines -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (4- { [2- methoxyl groups -5- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
1- (4- { [(1S, 2S, 4R)-two ring [2.2.1] hept- 2- yls] amino-sulfonyl } phenyl) -3- (pyridin-3-yl first Base) urea；
3- { 4- [(2R, 6S) -2,6- thebaine -4- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { imidazo [1,2-a] pyridine -6- ylmethyls } -1- { 4- [4- (morpholine -4- bases) piperidines -1- sulfonyls] phenyl } Urea；
1- { 4- [(2R, 6S) -2,6- thebaine -4- sulfonyls] phenyl } -3- { imidazo [1,2-a] pyridine -6- bases Methyl } urea；
3- { 4- [(the chloro- 5- aminomethyl phenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(naphthalene -1- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methoxyl group -2- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (benzenesulfonyl) phenyl] -3- { imidazo [1,2-a] pyridine -6- ylmethyls } urea；And
1- { 4- [(4- fluorophenyls) sulfonyl] phenyl } -3- { imidazo [1,2-a] pyridine -6- ylmethyls } urea.
In summary, the present invention relates to following aspect：
1. formula III A compounds and its pharmaceutical salts：
Wherein：
RaFor 1,2,3 or 4 and it may be selected from hydrogen, amino, oxo, halogen, alkoxy, alkyl, haloalkyl ,-N (alkyl )2,-NH (CO) O- alkyl, 1H- pyrazolyls, 1H- imidazole radicals and-C (O) NH2；And wherein described pyridine radicals can be included by its N originals The N- oxides that sub- member is formed；
R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl and R4For alkyl, hydroxy alkyl ,-S (O)2Alkyl ,- (CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl；
Haloalkyl；
Cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；
The wherein each cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl for it is unsubstituted or by 1,
2nd, 3,4 or 5 substituent substitutions, the substituent is identical or different and is independently selected from：Halogen, cyano group, alkyl, hydroxyl Base, hydroxy alkyl, hydroxy alkoxy base, haloalkyl, alkoxy, alkyl alkoxy, halogenated alkoxy, aryl alkenyl-, aryl oxide Base, benzyl epoxide, oxo ,-(CH2)q-NRbRc、-(CH2)q-CONRbRc、-S(O)2- alkyl ,-S (O)2NH- alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3,-C (O) alkyl ,-C (O) aryl ,-C (O) alkenyl aryl ,-C (O) O- alkyl ,-(CH2)qCycloalkanes Base, cycloalkyl alkoxy-, aryl, aryl alkyl-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl；
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, haloalkyl, alkyl halides One or more of epoxide, oxo, cyano group, alkyl, haloalkyl or alkoxy replace；
RbAnd RcIt is independently selected from H, alkyl, hydroxy alkyl, alkoxy, aryl, alkoxyalkyl ,-S (O)2Alkyl and cycloalkanes Base, or RbAnd Rc5 or 6 circle heterocycles alkyl are formed together with the nitrogen-atoms that can be connected with them, wherein the Heterocyclylalkyl can contain There are one or more additional heteroatoms selected from N, S or O；
Q is 0 or 1；
Condition is that the formula III A compounds are not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea；
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide；Or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
2. 1 compound and its pharmaceutical salts, wherein：
RaFor 1,2,3 or 4 and it may be selected from hydrogen, amino, oxo, halogen, (C1-C6) alkoxy, (C1-C6) alkyl, halo (C1-C6) alkyl ,-N (C1-C6- alkyl)2、-NH(CO)O-(C1-C6) alkyl, 1H- pyrazolyls, 1H- imidazole radicals and-C (O) NH2； And wherein described pyridine radicals can include the N- oxides formed by its N atomic component；
R1For-NR3R4, wherein R3For H, C1-C6- alkyl or-S (O)2(C1-C6) alkyl, and R4For (C1-C6) alkyl, hydroxyl Base (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl；
Halo (C1-C6) alkyl；
C3-C12- cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；
Wherein：
The each cycloalkyl, aryl or heteroaryl be unsubstituted or by 1,2,3,4 or 5 substituents replace, it is described Substituent is identical or different and is independently selected from following：Halogen, cyano group, (C1-C6) alkyl, hydroxyl, hydroxyl (C1-C6) alkyl, hydroxyl (C1-C6) alkoxy, halo (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl (C1-C6) alkoxy, halo (C1-C6) Alkoxy, aryl (C2-C6) alkenyl-, aryloxy, benzyl epoxide, oxo ,-(CH2)q-NRbRc、-(CH2)q-CONRbRc、-S (O)2-(C1-C6) alkyl ,-S (O)2NH-(C1-C6) alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3、-C(O)(C1-C6) alkane Base ,-C (O) aryl ,-C (O) (C2-C6) alkenyl aryl ,-C (O) O- (C1-C6) alkyl ,-(CH2)qCycloalkyl, cycloalkyl (C1-C6) Alkoxy-, aryl, aryl (C1-C6) alkyl-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl, wherein each cycloalkanes Base, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, halo (C1-C6) alkyl, halo (C1-C6) alkoxy, oxygen Generation, cyano group, (C1-C6) alkyl, halo (C1-C6) alkyl or (C1-C6) substitution of one or more of alkoxy；
RbAnd RcIt is independently selected from H, (C1-C6) alkyl, hydroxyl (C1-C6) alkyl, (C1-C6) alkoxy, aryl, (C1-C6) alkane Epoxide (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl and (C3-C6) cycloalkyl, or RbAnd RcThe nitrogen that can be connected with them is former Son forms 5 or 6 circle heterocycles alkyl together, wherein the Heterocyclylalkyl can contain one or more extra miscellaneous originals selected from N, S or O Son；
Q is 0 or 1；
Wherein Heterocyclylalkyl be containing 1, the heteroatomic 5-13 circle heterocycles alkyl that 2,3 or 4 are selected from N, O and S；Heteroaryl For containing 1, the heteroatomic 5-13 unit's heteroaryls that 2,3 or 4 are selected from N, O and S；And
Condition is that the formula III A compounds are not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea,
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide, or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
3. 1 or 2 compound, wherein R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkane Base, hydroxy alkyl ,-S (O)2Alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl Base.
4. 3 compound, wherein R1For-NR3R4, wherein R3For H, and R4For aryl.
5. 1 or 2 compound, wherein R1For haloalkyl.
6. 5 compound, wherein R1For trifluoromethyl.
7. 1 or 2 compound, wherein R1For unsubstituted or substituted C3-C12- cycloalkyl.
8. 7 compound, wherein cycloalkyl are selected from cyclopropyl, cyclopenta, suberyl, azaspiro [4.5] decyl, two rings [2.2.1] heptyl, two rings [3.1.1] heptyl, adamantyl and (1S, 2S, 3S, 5R) -2,6,6- trimethyls two ring [3.1.1] heptan Base.
9. 1 or 2 compound, wherein R1For unsubstituted or substituted C6-C10- aryl.
10. 9 compound, wherein R1Selected from phenyl, naphthyl, tetralyl and 1H- indenes -5- bases.
11. 1 or 2 compound, wherein R1For unsubstituted or substituted Heterocyclylalkyl.
12. 11 compound, wherein R1For it is unsubstituted or substituted containing 1, the miscellaneous original that 2 or 3 are selected from N, O and S The 5-12 circle heterocycles alkyl of son.
13. 12 compound, wherein Heterocyclylalkyl be selected from azetidinyl, piperidyl, pyrrolidinyl, piperazinyl, Thiomorpholine base, 2,8- diaza spiros [5.5] undecyl, 8- oxa- -3- azabicyclics [3.2.1] octyl group, 1,4- diazacyclos Heptane base, 2- oxa- -8- azaspiros [4.5] decyls and decahydroquinolyl.
14. 1 or 2 compound, wherein R1For unsubstituted or substituted heteroaryl.
15. 14 compound, wherein R1For it is unsubstituted or substituted containing 1, the miscellaneous original that 2 or 3 are selected from N, O and S The 5-12 unit's heteroaryls of son.
16. 15 compound, wherein R1Selected from 1,3,4- oxadiazolyls, (1R) -3- oxo -3H- spiral shell [2- benzo furans Mutter -1,3'- pyrrolidines] base, 3,4- dihydro -2H-1,4- benzoxazinyls, oxo -2,3- dihydro -1H- indyls, 3,4- bis- Hydrogen -2H-1,5- benzo dioxasBase, 1,2,3,4- tetrahydro isoquinolyls, indyl, indazolyl, thienyl, pyrazolyl, pyrrole Piperidinyl, pyrimidine radicals, 1,2- oxazolyls, 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkene of 3,5,10,12- six Base, 5- oxo -5,6,7,8- naphthane -1- bases, phenoxthine base, 3- azaspiros [5.5] undecyl, aza-tricycle [7.3.1.05,13] 13 carbon -1 (13), the alkenyls of 5,7,9,11- five, (4aR, 8aS)-Decahydroisoquinolinpreparation base and 5,6,7,8- tetra- Hydrogen -1,6- phthalazinyls.
17. compound, is selected from：
1- (pyridin-3-yl methyl) -3- (4- { [2- (trifluoromethoxy) phenyl] sulfonyl } phenyl) urea；
3- { 4- [(4- bromophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- methyl -4- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
N- [2- (pyridin-3-yl) ethyl] -4- { [3- (trifluoromethoxy) phenyl] sulfonyl } benzamide；
3- { 4- [(4- methoxyl group -2- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4- Dimethoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [(6- aminopyridine -3- bases) methyl] -3- { 4- [(4- fluorophenyls) sulfonyl] phenyl } urea；
3- { 4- [(3,5- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [(6- aminopyridine -3- bases) methyl] -3- [4- (benzenesulfonyl) phenyl] urea；
3- { 4- [(4- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- { [6- (1H- pyrazol-1-yls) pyridin-3-yl] methyl } urea；
3- (4- { [the fluoro- 4- of 2- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
4- (benzenesulfonyl)-N- { imidazo [1,2-a] pyridin-7-yl methyl } benzamide；
3- { 4- [(2- bromophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
4- (benzenesulfonyl)-N- (pyridin-3-yl methyl) benzamide；
3- { 4- [(2- ethoxyl phenenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- { [6- (1H- imidazoles -1- bases) pyridin-3-yl] methyl } urea；
3- { 4- [(3,4- Dimethoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { [({ 4- [(4- chlorphenyls) sulfinyl] phenyl } carbamoyl) amino] methyl } pyridine -1--1- oxygen Compound；
1- (pyridin-3-yl methyl) -3- (4- { [4- (trifluoromethyl) phenyl] sulfonyl } phenyl) urea；
3- { 4- [(2,5- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [3- (trifluoromethoxy) phenyl] sulfonyl } phenyl) urea；
N, N- dimethyl -4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzoyl Amine；
3- (4- { [2- methoxyl groups -4- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- [4- (benzenesulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
1- [4- (benzenesulfonyl) phenyl] -3- (1H- pyrazole-3-yls methyl) urea；
3- { 4- [(3- bromophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [3- (trifluoromethyl) phenyl] sulfonyl } phenyl) urea；
N- { imidazo [1,2-a] pyridine -6- ylmethyls } -4- { [3- (trifluoromethoxy) phenyl] sulfonyl } benzoyl Amine；
1- { [4- (benzenesulfonyl) phenyl] methyl } -3- (quinoline -6- bases) urea；
3- { 4- [(5- fluoro-2-methylbenzenes base) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- { [6- (dimethylamino) pyridin-3-yl] methyl } urea；
3- { 4- [(4- chloro-2-methyls phenyl) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 3- methoxyphenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,3- difluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 3- aminomethyl phenyls of the chloro- 6- of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (pyrimidine -5- sulfonyls) phenyl] urea；
3- { 4- [(3,5- difluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [6- (benzenesulfonyl) pyridin-3-yl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4 dichloro benzene base) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- methoxyphenyls of 2,5- bis-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [(3- aminophenyls) methyl] -3- [4- (benzenesulfonyl) phenyl] urea；
3- { 4- [(4- ethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- chlorphenyls) sulfinyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- chlorphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2- fluorophenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- chlorphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 2- methoxyphenyls of 5-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (2- methoxynaphthalene -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { [({ 4- [(4- chlorphenyls) sulfonyl] phenyl } carbamoyl) amino] methyl } pyridine -1--1- is aoxidized Thing；
3- { 4- [(3- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (2H-1,3- benzodioxole -5- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
4- [(2- chlorphenyls) sulfonyl]-N- { imidazo [1,2-a] pyridine -6- ylmethyls } benzamide；
4- [(3- chlorphenyls) sulfonyl]-N- { imidazo [1,2-a] pyridine -6- ylmethyls } benzamide；
3- { 4- [(3- chlorphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- (methoxy) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- { [6- (2- methoxy ethoxies) pyridin-3-yl] methyl } urea；
3- { 4- [(2,3- dichlorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluoro-2-methylbenzenes base) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2- Phenoxyphenyls) sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
1- [4- (benzenesulfonyl) phenyl] -3- { 5H, 6H, 7H, 8H- imidazo [1,2-a] pyridine -6- ylmethyls } urea；
3- (4- { [3- (propyl- 2- yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- acetylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (benzenesulfonyl) phenyl] -3- { imidazo [1,2-a] pyridine -6- ylmethyls } urea；
3- { 4- [(2,3- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (pentamethylene sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 6- methoxyphenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [the fluoro- 4- of 3- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- (quinoline -6- bases) urea；
3- { 4- [(2,5- Dimethoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- [4- (trifluoromethyl) sulfonvlphenyl] urea；
3- { 4- [(the fluoro- 4- methoxyphenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(4- fluorophenyls) sulfonyl] phenyl } -3- { imidazo [1,2-a] pyridine -6- ylmethyls } urea；
3- [4- (3,5- dimethyl -1,2- oxazole -4- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 3- fluorophenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- { imidazo [1,2-a] pyridine -6- ylmethyls } -4- { [3- (trifluoromethyl) phenyl] sulfonyl } benzamide；
3- (4- { [2- chloro- 5- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
4- [(3,5- difluorophenyls) sulfonyl]-N- { imidazo [1,2-a] pyridine -6- ylmethyls } benzamide；
1- (pyridin-3-yl methyl) -3- (4- { [2- (trifluoromethyl) phenyl] sulfonyl } phenyl) urea；
3- (4- { [4- chloro- 3- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- methanesulfonylphenYls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- aminomethyl phenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [the chloro- 6- of 2- (propyl- 2- yls) pyridine -3- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methoxyl group -5- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (pyridine -4- sulfonyls) phenyl] urea；
N- { imidazo [1,2-a] pyridine -6- ylmethyls } -4- [(3- methoxyphenyls) sulfonyl] benzamide；
3- { 4- [(the chloro- 4- fluorophenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- ethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- aminomethyl phenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,5- dichlorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (pyridine -3- sulfonyls) phenyl] urea；
3- { 4- [(3- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4 difluorobenzene base) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,6- Dimethoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { 8- oxatricyclos [7.4.0.02,7] 13 carbon -1 (9), 2 (7), the alkene -6- sulfonyls of 3,5,10,12- six Phenyl) -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (pyridine-2-sulfuryl base) phenyl] urea；
N- (1,3- benzothiazol-6-yls methyl) -4- [(3- chlorphenyls) sulfonyl] benzamide；
3- { 4- [(the chloro- 2- methoxyphenyls of 5-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- methoxyl groups -5- (propyl- 2- yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (propyl- 2- bases epoxide) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(2,4,6- trimethylphenyls) sulfonyl] phenyl } urea；
3- { 4- [(the fluoro- 4- methoxyphenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (benzenesulfonyl) phenyl] -3- { thieno [2,3-c] pyridine -2- ylmethyls } urea；
3- { 4- [(2,4- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,5- difluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 5- aminomethyl phenyls of 2-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [4- (trifluoromethoxy) phenyl] sulfonyl } phenyl) urea；
3- [4- (1- methyl isophthalic acid H- pyrazoles -4- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- [4- (5- methylthiophene -2- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,4- difluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- benzoylphenyls) -3- (pyridin-3-yl methyl) urea；
3- [4- (benzenesulfonyl) phenyl] -1- (pyridin-3-yl) urea；
3- { 4- [(2,6- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
4- (benzenesulfonyl)-N- (pyridin-3-yl) benzamide；
4- (benzenesulfonyl)-N- (pyridin-4-yl) benzamide；
3- [4- (2- methoxy pyrimidine -5- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3- methoxyphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- methoxyl group -2- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (phenylaminosulfonyl group) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4- fluorophenyls of 3-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 8- methyl -2,8- diaza spiros [5.5] hendecane -2- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) Urea；
1- (pyridin-3-yl methyl) -3- (4- { 4- [4- (trifluoromethyl) phenyl] piperazine -1- sulfonyls } phenyl) urea；
3- { 4- [(3,4- difluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- methyl -5- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyridine -2- formyls Amine；
3- { 4- [(2R) -2- (methoxy) pyrrolidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [the fluoro- 5- of 3- (2,2,2- trifluoro ethoxies) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- { 4- [(4- chloro-2-methyls phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (3- methoxyphenyls) amyl- 3- yls] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- propoxyphenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- fluoro- 3- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- methoxyl group -3- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- chloro- 3- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [6- (dimethylamino) pyridine -3- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- (morpholine -4- bases) -5- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl first Base) urea；
1- [4- (3,5- lupetidine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
(2S)-N, N- dimethyl -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrrole Cough up alkane -2- formamides；
4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperazine -1- carboxylate methyl esters；
3- { 4- [(2- methoxy ethyls) (methyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [4- (2H-1,3- benzodioxole -5- bases) piperazine -1- sulfonyls] phenyl } -3- (pyridine -3- Ylmethyl) urea；
3- { 4- [(2- methoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- (propyl- 2- yls) -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzoyl Amine；
3- (4- { [(2- methoxyphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (1- Methyl-1H-indole -2- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { [4- (piperidines -1- sulfonyls) phenyl] methyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- aminomethyl phenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (cyclo-heptylamino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
1- { 4- [4- (pyrazine -2- bases) piperazine -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(5- picoline -3- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2- methoxyphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [ring [3.1.1] hept- 3- of (1R, 2R, 3R, 5S) -2,6,6- trimethyls two Base] amino-sulfonyl } phenyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { 4- [6- (trifluoromethyl) pyridine -2- bases] piperazine -1- sulfonyls } phenyl) Urea；
3- { 4- [(3- ethyoxyl -4- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2- aminomethyl phenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(6- ethylpyridine -2- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [3- (2- methoxy ethyls) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (1- methyl isophthalic acid H- indazole -7- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- methoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- cyclopropyl -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzamide；
3- { 4- [(4- methoxyl group -3,5- 3,5-dimethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- methyl -4- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { imidazo [1,2-a] pyridine -6- ylmethyls } -1- { 4- [4- (morpholine -4- bases) piperidines -1- sulfonyls] phenyl } Urea；
3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyrimidine -5- ylmethyls) urea；
3- (4- { [2- (3- methoxyphenyls) ethyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
N- [(3R) -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrrolidines -3- Base] acetamide；
1- { 4- [(4- phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4 difluorobenzene base) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (dimethylamino-sulfonyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methoxyl group -6- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methanesulfonylphenYls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2- fluorophenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- methyl -2- { 4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperazine -1- Base } acetamide；
3- { 4- [(the chloro- 2- methoxyl groups -5- aminomethyl phenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- chloro- 5- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(1,5- dimethyl -1H- pyrazole-3-yls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (2- methoxy ethoxies) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,4- 3,5-dimethylphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { methyl [(1S) -1- phenylethyls] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { 8- azaspiros [4.5] decane -8- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2- fluorophenyls of 5-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,5- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (piperidines -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
1- { 4- [(3S) -3- cyano piperidine -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2S) -2- (methoxy) pyrrolidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
N- { imidazo [1,2-a] pyridine -6- ylmethyls } -4- { 8- oxa- -3- azabicyclics [3.2.1] octane -3- sulphonyl Base } benzamide；
1- { 4- [(5- oxo -5,6,7,8- naphthane -1- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) Urea；
1- (4- { 4- [2- (morpholine -4- bases) -2- oxoethyls] piperazine -1- sulfonyls } phenyl) -3- (pyridin-3-yl first Base) urea；
1- { 4- [(3- benzoylphenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(6- methoxypyridine -3- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- chloro-4-methoxies phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- ethyls -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzamide；
3- (4- { [4- (2- methoxy ethoxies) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (6- methoxynaphthalene -2- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [4- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [cyclohexyl (methyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- (4- chlorophenoxies) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- ethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- ({ 4- [(pyrrolidin-1-yl) carbonyl] phenyl } sulfonyl) phenyl] urea；
3- (4- { [3- (2- hydroxyethyls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2,6- 3,5-dimethylphenyls of 3-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,5- 3,5-dimethylphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (3- methyl piperidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (4- bromophenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- picoline -4- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- fluoro-2-methylbenzenes base) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [(3,4- difluorophenyls) methyl] -3- [4- (piperidines -1- sulfonyls) phenyl] urea；
N- (pyridin-3-yl methyl) carbamic acid 4- (piperidines -1- sulfonyls) phenylester；
3- { 4- [(4- methoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [2- (3,4- dichlorophenyls) acetyl group] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- [4- ({ 2- [(2S) -2- hydroxy propyloxy groups] phenyl } amino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) Urea；
1- [4- (1H- indoles -7- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 5- aminomethyl phenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- (ethoxyl methyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [(1- phenylcyclopentyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [3- (trifluoromethyl) piperidines -1- sulfonyls] phenyl } urea；
1- { 4- [(3- phenyls) sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3,4- dichlorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(pyridine -2- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
(3S)-N, N- diethyl -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperazine Pyridine -3- formamides；
3- (pyridin-3-yl methyl) -1- [4- (quinoline -6- sulfonyls) phenyl] urea；
1- (4- { [(1S, 2S, 4R)-two ring [2.2.1] hept- 2- yls] amino-sulfonyl } phenyl) -3- (pyridin-3-yl first Base) urea；
3- [(5- chloropyridine -3- bases) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- { 4- [4- (3- chlorphenyls) -4- cyano piperidine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (4- Nmethanesulphonylpiperazine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- [4- (1H- pyrroles -1- sulfonyls) phenyl] urea；
3- { 4- [(4- ethyoxyl -2- fluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- propyl group phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- cyano group -4- (4- methoxyphenyls) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [(4- chlorphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [3- (piperidines -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3- fluorophenoxies) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(pyridin-3-yl) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (thiomorpholine -4- sulfonyls) phenyl] urea；
3- (4- { [2- chloro- 5- (trifluoromethoxy) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (pyrrolidines -1- sulfonyls) phenyl] urea；
2- methyl-N- { 3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] phenyl } third Acid amides；
1- [4- (Cyclohexylamino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- [4- (piperidines -1- sulfonyls) phenyl] -1- [1- (pyridin-3-yl) ethyl] urea；
1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperidines -4- formamides；
3- { 4- [(2- tert-butyl-phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [(4- methoxyphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 5- aminomethyl phenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- fluoro- 3- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { 3- [(2- oxo-pyrrolidine -1- bases) methyl] piperidines -1- sulfonyls } phenyl) -3- (pyridin-3-yl first Base) urea；
1- (4- { [2- (morpholine -4- bases) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(2,4,6- trimethylphenyls) amino-sulfonyl] phenyl } urea；
3- [4- (piperidines -1- sulfonyls) phenyl] -1- [2- (pyridin-3-yl) ethyl] urea；
1- [4- (4- cyclohexylpiperazin -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4- fluorophenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 2- methoxyphenyls of 5-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (methylaminosulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
1- [4- (phenoxthine -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- dichlorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2R, 6S) -2,6- thebaine -4- sulfonyls] phenyl } -3- { imidazo [1,2-a] pyridine -6- bases Methyl } urea；
N- (propyl- 2- yls) -2- { 4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperazines Piperazine -1- bases } acetamide；
N, N- diethyl -2- { 4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperazines Piperazine -1- bases } acetamide；
3- (pyridin-3-yl methyl) -1- [4- (quinoline -8- sulfonyls) phenyl] urea；
1- (4- { [4- (piperidin-1-yl) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3,5- dichloropyridine -4- bases) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (Cyclobutylamino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- [4- (4- methyl piperidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { 4- [4- (trifluoromethyl) pyridine -2- bases] piperazine -1- sulfonyls } phenyl) Urea；
1- { 4- [4- (morpholine -4- bases) piperidines -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
1- [4- (4- benzyl -1,4- Diazesuberane -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
N- [(3S) -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrrolidines -3- Base] acetamide；
3- (pyridin-3-yl methyl) -1- [4- (quinoline -3- sulfonyls) phenyl] urea；
3- (4- { [the fluoro- 5- of 3- (2- methyl propoxyl group) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
N, N- dimethyl -2- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzene first Acid amides；
1- { 4- [(3- cyano-phenyls) sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- [(5- fluorine pyridin-3-yl) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
1- { 4- [(2H-1,3- benzodioxole -5- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl first Base) urea；
1- [4- (isoquinolin -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4- aminomethyl phenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { 3- azaspiros [5.5] hendecane -3- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,4 difluorobenzene base) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (diethylamino sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
N- (2- methyl-propyls) -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
3- (4- { [3- (difluoro-methoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- methoxyl groups -5- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- { 4- [4- (2- ethoxyl phenenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
N- ethyls -4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzamide；
3- [4- (6- methoxypyridine -3- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (propyl- 2- bases epoxide) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [(3- phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (4- { [(3- fluorophenyls) methyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- propoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [4- (trifluoromethyl) piperidines -1- sulfonyls] phenyl } urea；
3- { 4- [(3- ethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- (propyl- 2- bases epoxide) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [4- (benzylaminosulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(4- ethoxyl phenenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methoxypyridine -3- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (4,4- difluoropiperdin -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3S) -3- methyl -4- (4- aminomethyl phenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) Urea；
3- [4- (1- methyl isophthalic acid H- indazole -4- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- { 4- [4- (piperidin-1-yl) piperidines -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- [4- (butylamino sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- picoline -2- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,4- Dimethoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(3- cyano-phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3- chlorphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (dimethylamino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [mesyl (piperidin-4-yl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [(4- fluorophenyls) carbonyl] piperidines -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [4- (piperazine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3S) -4- (4- methoxyphenyls) -3- methyl piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl first Base) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(3S) -3- (trifluoromethyl) piperidines -1- sulfonyls] phenyl } urea；
3- { 4- [methyl (ring -3- bases of oxa- penta) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (2,3- dihydro -1- benzofuran -7- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2- methoxy ethyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (2,3- dihydro -1,4- benzo Dioxin -6- sulfonyls) phenyl] -3- (pyridin-3-yl first Base) urea；
3- (4- { [4- (difluoro-methoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- methyl -4- (propyl- 2- yls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [methyl ({ [5- (trifluoromethyl) pyridine -2- bases] methyl }) amino-sulfonyl] phenyl } -1- (pyridine -3- Ylmethyl) urea；
1- (4- { 4- [3- (morpholine -4- bases) propyl group] piperazine -1- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (4- { [3- (propyl- 1- sulfonamidos) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2,3- dihydro -1,4- benzo Dioxin -6- bases) amino-sulfonyl] phenyl } -3- (pyridine - 3- ylmethyls) urea；
3- { 4- [4- (5- chloro-2-methyls phenyl) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(naphthalene -1- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (4- { [3- chloro- 4- (trifluoromethoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [4- (2H-1,3- benzodioxole -5- ylmethyls) piperazine -1- sulfonyls] phenyl } -3- (pyrroles Pyridine -3- ylmethyls) urea；
N- Methyl-N-phenyls -2- { 4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] Piperazine -1- bases } acetamide；
1- (4- { 4- [(furans -2- bases) carbonyl] piperazine -1- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (the chloro- 2- methoxyphenyls of 5-) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (propyl- 2- yls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- fluorine pyridin-3-yl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (2- methyl -3- oxypiperazin -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- ethoxyl phenenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,6- 3,5-dimethylphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- chlorphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (1H- indoles -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
The chloro- N of 3-, N- diethyl -5- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
3- [the fluoro- 4- of 2- (piperidines -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
N, N- dimethyl -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzoyl Amine；
1- (pyridin-3-yl methyl) -3- [4- ({ [3- (trifluoromethyl) phenyl] methyl } amino-sulfonyl) phenyl] urea；
N- [4- (piperidines -1- sulfonyls) phenyl] anginin -3- ylmethyl esters；
1- (4- { [3- (piperidin-1-yl) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (4- { [2- (2- hydroxyethyls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- benzyls -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- { 4- [(2- hydroxyethyls) (methyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [4- (trifluoromethyl) sulfonvlphenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [(4- chlorphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- second sulfonamidos phenyl) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (the chloro- 3- methoxyphenyls of 4-) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (1- methyl isophthalic acid H- indazole -6- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methyl-propyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- (2- hydroxyethyls) -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
3- { 4- [(3- chloro-2-methyls phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- fluoro- 4- (trifluoromethoxy) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- chloro-4-methoxies phenyl) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [the fluoro- 3- of 4- (2,2,2- trifluoro ethoxies) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
1- [4- (morpholine -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- (4- { [(4- chlorphenyls) methyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [methyl (2- methyl-propyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- chlorphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { methyl [(1R) -1- phenylethyls] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2- chlorphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- ({ 2- [(1S) -1- hydroxyethyls] phenyl } amino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(quinoline -6- bases) amino-sulfonyl] phenyl } urea；
3- { 4- [(2,5- difluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { [2- (piperidin-1-yl) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3- tert-butyl-phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { methyl [2- (4- aminomethyl phenyls) ethyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,6- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(1,3,5- trimethyl -1H- pyrazoles -4- bases) amino-sulfonyl] phenyl } Urea；
1- (4- { 3- aza-tricycles [7.3.1.05,13] 13 carbon -1 (13), 5,7,9,11- pentaene -3- sulfonyls benzene Base) -3- (pyridin-3-yl methyl) urea；
N, N- dimethyl -2- { 4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzene Base } acetamide；
3- [(6- chloropyridine -3- bases) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- (4- { [(5- methylfuran -2- bases) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { 4- [2- oxos -2- (piperidin-1-yl) ethyl] piperazine -1- sulfonyls } phenyl) -3- (pyridin-3-yl first Base) urea；
1- (pyridin-3-yl methyl) -3- [4- (3,3,5- trimethyl azepan -1- sulfonyls) phenyl] urea；
3- (4- { [3- (3,5- dimethyl -1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- (4- { [3- (methoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (1- propyl group -1H- pyrazoles -4- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- fluoro- 5- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { [2- (morpholine -4- ylmethyls) phenyl] sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
N- [4- (pyridin-3-yl) -1,3- thiazol-2-yls] -4- (1,2,3,4- tetrahydroisoquinoline -2- sulfonyls) benzoyl Amine；
4- { [(pyridin-3-yl methyl) carbamoyl] amino } methyl benzoate；
3- (4- { [2- (propyl- 2- yls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (propyl- 2- yls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [the fluoro- 4- of 3- (2,2,2- trifluoro ethoxies) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
1- (pyridin-3-yl methyl) -3- { 4- [(3,4,5- trifluorophenyls) amino-sulfonyl] phenyl } urea；
1- { 4- [(pyridine -2- ylmethyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
The fluoro- 3- of N, N- diethyl -4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
1- (4- { [4- (piperidines -1- sulfonyls) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2,4 dichloro benzene base) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (ethylaminosulfonyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [4- (4- cyano piperidine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2,2- dimethyl propyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (dibenzyl amino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
(2S) -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrrolidines -2- formyls Amine；
1- (4- { 3- oxa- -8- azabicyclics [3.2.1] octane -8- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) Urea；
1- { 4- [(1H- indazole -5- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
N- { 5- [({ [4- (piperidines -1- sulfonyls) phenyl] carbamoyl } amino) methyl] pyridine -2- bases } amino first Tert-butyl acrylate；
3- { 4- [benzyl (methyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3- chloropyridine -2- bases) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- (propyl- 2- bases epoxide) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methanesulfonylaminophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
The fluoro- 5- of N, N- diethyl -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
3- (4- { [4- (methoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
N, N- dimethyl -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperidines -4- Formamide；
3- { 4- [(propyl- 2- yls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- ({ 3- [(morpholine -4- bases) carbonyl] phenyl } sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- (4- { [(4- fluorophenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- ethoxyl phenenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [benzyl (propyl- 2- yls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- ({ [4- (dimethylamino) phenyl] methyl } amino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [benzyl (ethyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- acetylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (4- { [ring -2- bases of (2R)-oxa- penta] carbonyl } piperazine -1- sulfonyls) phenyl] -3- (pyridin-3-yl first Base) urea；
2- methyl-N- { 1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperidines -4- Base } propionamide；
1- (pyridin-3-yl methyl) -3- (4- { [4- (trifluoromethoxy) phenyl] amino-sulfonyl } phenyl) urea；
3- (pyridin-3-yl methyl) -1- (4- { [4- (pyrrolidin-1-yl) phenyl] amino-sulfonyl } phenyl) urea；
3- (4- { [(3- chlorphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (ethylsulfonyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (4- hydroxy piperidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- (hydroxymethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- acetylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- ethoxyl phenenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
The fluoro- N- of 4- (propyl- 2- yls) -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] Benzamide；
3- { 4- [4- (3- chlorphenyls) -4- hydroxy piperidine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3S) -3- methyl -4- (3- aminomethyl phenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) Urea；
3- { 4- [(the chloro- 3- methoxyphenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,3- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,3- dichlorophenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (4- benzyl piepridine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
1- (4- { [(4- phenyls) methyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(5,6,7,8- naphthane -1- bases) amino-sulfonyl] phenyl } urea；
Rel-3- { 4- [(2R, 6S) -2,6- thebaine -4- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (decahydroquinoline -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 2- methoxyphenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(4- ethynyl phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4- aminomethyl phenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4,6- 3,5-dimethylphenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [3- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2R) -2- benzyl piepridine -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- [4- (piperidines -1- sulfonyls) phenyl] -1- (pyrazine -2- ylmethyls) urea；
3- { 4- [(the fluoro- 3- aminomethyl phenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(3,4- dihydro -2H-1,5- benzo dioxas- 7- bases) amino-sulfonyl] phenyl } -3- (pyridine -3- Ylmethyl) urea；
3- { 4- [4- (diethylamino) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluorophenyls) (methyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (2- picoline -3- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- { 4- [6- (morpholine -4- bases) pyridine -3- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 5- methoxyphenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { imidazo [1,2-a] pyridine -6- ylmethyls } -1- (4- { 3- oxa- -8- azabicyclic [3.2.1] octanes -8- Sulfonyl } phenyl) urea；
3- { 4- [(the fluoro- 4- aminomethyl phenyls of 3-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
Rel-3- { 4- [(4aR, 8aS)-Decahydroisoquinolinpreparation -2- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (4- methanesulphonylpiperidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(2S) -2- (pyrrolidin-1-yl methyl) pyrrolidines -1- sulfonyls] phenyl } Urea；
3- { 4- [(6- picoline -2- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [(morpholine -4- bases) carbonyl] piperidines -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [3- (the chloro- 4- fluorophenoxies of 2-) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [4- chloro- 3- (trifluoromethyl) phenyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- (4- { [3- (2- methyl propoxyl group) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [two (4- fluorophenyls) methyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (1- methyl isophthalic acid H- indazole -5- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (4- { [3- (benzyl epoxide) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- (4- { [3- (pyrrolidin-1-yl) phenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [(4- ethyoxyl -3- fluorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- dichlorophenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3,4- 3,5-dimethylphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [3- (trifluoromethoxy) phenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [(2- ethoxyl phenenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methanesulfonylphenYls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methoxyl group -4- aminomethyl phenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (6- picoline -3- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- [4- (5,6,7,8- tetrahydrochysene -1,6- benzodiazine -6- sulfonyls) phenyl] urea；
3- [4- (2,4- dimethoxypyridin -5- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- methoxyl group -2- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- (propyl- 2- yls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- chloro-2-methyls phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [(2- fluorophenyls) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- (4- { [2- (4- fluorophenoxies) pyridin-3-yl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- { 4- [(4- Phenoxyphenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(pyridin-4-yl methyl) amino-sulfonyl] phenyl } urea；
1- { 4- [4- (azepan -1- bases) piperidines -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzamide；
1- (4- { [4- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
1- { 4- [(cyclohexyl methyl) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(4- ethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- bromophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [(6- aminopyridine -3- bases) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- { 4- [(3,4- dichlorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- tert-butyl-phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [4- (2- oxo -2,3- dihydro -1H- indoles -1- bases) piperidines -1- sulfonyls] phenyl } -3- (pyridine -3- Ylmethyl) urea；
1- [(6- isocyano groups pyridin-3-yl) methyl] -3- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- (4- { [2- (3- chlorphenyls) ethyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 3- methoxyphenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { [3- (1H- pyrazol-1-yls) phenyl] sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [3- (pyrrolidin-1-yl) pyrrolidines -1- sulfonyls] phenyl } urea；
1- [4- (2H-1,3- benzodioxole -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [3- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [methyl (2- phenylethyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [4- (3,4- dihydro -2H-1,4- benzoxazine -4- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3S) -3- methyl piperidine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- [(4- fluorophenyls) methyl] -3- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- [4- (tert-butylamino sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
1- [4- (4- phenylpiperazine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (5- methylpyrimidine -2- bases) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (azepan -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [2- (trifluoromethoxy) phenyl] amino-sulfonyl } phenyl) urea；
3- (4- { [3- chloro- 4- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- acetylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (the bromo- 3- methoxyphenyls of 4-) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (piperidines -1- sulfonyls) phenyl] -1- { [6- (trifluoromethyl) pyridin-3-yl] methyl } urea；
3- [4- (5- fluorine pyridine -3- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (4- { 2- oxa- -8- azaspiros [4.5] decane -8- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
1- { 4- [4- (2- phenyl acetyls) piperazine -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
1- { 4- [4- (3- phenyl propyl- 2- alkene -1- bases) piperazine -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(3- aminosulfonvlphenyls) sulfonyl] phenyl } urea；
N- methyl -2- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzamide；
3- (4- { [4- (propyl- 2- bases epoxide) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- hydroxyethyls) (propyl- 2- yls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(adamantane -1- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
1- { 4- [(2R) -2- (morpholine -4- ylmethyls) piperidines -1- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3,5- dichlorophenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 5- aminomethyl phenyls of 2-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- { 3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] phenyl } acetamide；
N- methyl -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzamide；
3- { 4- [4- (4- chlorphenyls) -4- cyano piperidine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- methyl -3- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [4- (4- Phenylpiperidine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3- acetylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (methoxy) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
The fluoro- N of 3-, N- dimethyl -5- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzene Formamide；
N- [2- (pyridin-3-yl) ethyl] -4- { [3- (trifluoromethoxy) phenyl] amino-sulfonyl } benzamide；
3- { 4- [cyclohexyl (ethyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3,4- dichlorophenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 3- methoxyphenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- fluoro- 5- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (4- { [4- (propyl- 2- yls) phenyl] methyl } piperazine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) Urea；
1- (pyridin-3-yl methyl) -3- (4- { 4- [3- (trifluoromethyl) phenyl] piperazine -1- sulfonyls } phenyl) urea；
1- [4- (cyclopropylamino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
4- [(the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl]-N- [2- (pyridin-3-yl) ethyl] benzamide；
3- { 4- [(3- aminophenyls) (mesyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2,3- dihydro -1H- indenes -5- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (4- { [the chloro- 4- of 3- (morpholine -4- bases) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [2- (dimethylamino) pyrimidine -5- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [1- (3- methoxyphenyls) -4- methylcyclohexyls] piperazine -1- sulfonyls } phenyl) -1- (pyridine -3- Ylmethyl) urea；
3- (4- { [(5- ethylpyridine -2- bases) methyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- { 4- [(the chloro- 4- propoxyphenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- chloronaphthalene -1- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(5- acetyl group -2- methoxyphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(1R) -3- oxo -3H- spiral shells [2- benzofuran -1,3'- pyrrolidines] -1'- bases sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2,4- Dimethoxyphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { [4- (piperidines -1- sulfonyls) phenyl] methyl } -1- (pyridin-3-yl) urea；
N- { 1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] piperidin-4-yl } acetyl Amine；
3- (4- { [3- (methoxy) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 4- methoxyphenyls of 3-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2- phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
1- (4- { 4- [(2- oxo-pyrrolidine -1- bases) methyl] piperidines -1- sulfonyls } phenyl) -3- (pyridin-3-yl first Base) urea；
3- (4- { [2- (piperidin-1-yl) -5- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl first Base) urea；
3- (4- { [2- methoxyl groups -5- (trifluoromethyl) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- [4- (lupetidine -1- sulfonyls) phenyl] -3- (pyridin-3-yl methyl) urea；
1- { 4- [(1- phenylcyclohexyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [6- (trifluoromethyl) pyridine -3- sulfonyls] phenyl } urea；
3- { 4- [(4- picoline -3- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (2- methyl-propyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { 4- [2- oxos -2- (pyrrolidin-1-yl) ethyl] piperazine -1- sulfonyls } phenyl) -3- (pyridin-3-yls Methyl) urea；
1- (pyridin-3-yl methyl) -3- { 4- [(4- aminosulfonvlphenyls) amino-sulfonyl] phenyl } urea；
5- [({ [4- (piperidines -1- sulfonyls) phenyl] carbamoyl } amino) methyl] pyridine-2-carboxamide；
3- (4- { 4- [(4- tert-butyl-phenyls) methyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
3- [4- (azetidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- (4- { [2- (1H- pyrroles -1- bases) phenyl] amino-sulfonyl } phenyl) urea；
3- (4- { 4- [3- chloro- 5- (trifluoromethyl) pyridine -2- bases] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yls Methyl) urea；
N, N- diethyl -2- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzene first Acid amides；
1- { 4- [(piperidin-1-yl) carbonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
N- ethyls-N- [(3S) -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrroles Cough up alkane -3- bases] acetamide；
3- (pyridin-3-yl methyl) -1- { 4- [4- (pyrimidine -2-base) piperazine -1- sulfonyls] phenyl } urea；
3- { 4- [(3- ethylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [the chloro- 2- of 3- (morpholine -4- bases) pyridine -4- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- (4- { [ring [3.1.1] hept- 3- of (1S, 2S, 3S, 5R) -2,6,6- trimethyls two Base] amino-sulfonyl } phenyl) urea；
3- { 4- [(the fluoro- 3- aminomethyl phenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- phenyl propyl- 2- yls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { 4- [(1R) -1- (4- chlorphenyls) ethyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) Urea；
3- [4- (5- chloropyridine -3- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- [(3- fluorophenyls) methyl] -1- [4- (piperidines -1- sulfonyls) phenyl] urea；
3- { 4- [4- cyano group -4- (4- aminomethyl phenyls) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(3- Phenoxyphenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2,5- Dimethoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 5- aminomethyl phenyls of 3-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- methoxyl group -5- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(pyridin-3-yl methyl) amino-sulfonyl] phenyl } urea；
3- { 4- [4- (dipropylamino) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [(4- fluorophenyls) methyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- { 4- [(3S) -3- [(pyrrolidin-1-yl) carbonyl] piperidines -1- sulfonyls] phenyl } Urea；
3- { 4- [(3- bromophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(2- Phenoxyphenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- (4- { 4- [1- (4- chlorphenyls) ethyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
N, N- dimethyl -4- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzene first Acid amides；
1- { 4- [(4- phenyls) sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (4- aminomethyl phenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (4- acetyl group -1,4- Diazesuberane -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
N- cyclopenta -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] benzamide；
3- [4- (3,3- difluoro azetidine -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
1- (4- { [4- (morpholine -4- bases) phenyl] sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- [4- ({ 3- [(1S) -1- hydroxyethyls] phenyl } amino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- difluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- Dimethoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [ethyl (phenyl) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { [2- (trifluoromethyl) phenyl] amino-sulfonyl } phenyl) urea；
3- (4- { [3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl first Base) urea；
3- [4- ({ 4- [(1S) -1- hydroxyethyls] phenyl } amino-sulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- methoxyl group -2- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
4- [(3- chlorphenyls) amino-sulfonyl]-N- { imidazo [1,2-a] pyridine -6- ylmethyls } benzamide；
3- { 4- [(the 4- tert-butyl group -2- chlorphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { 8- azabicyclics [3.2.1] octane -8- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
1- [4- (clopentylamino sulfonyl) phenyl] -3- (pyridin-3-yl methyl) urea；
3- (4- { 4- [2- (diethylamino) ethyl] piperazine -1- sulfonyls } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (4- chlorphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- (3- fluorophenyls) ethyl] (methyl) amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [methyl ({ [3- (trifluoromethyl) phenyl] methyl }) amino-sulfonyl] phenyl } -1- (pyridin-3-yl first Base) urea；
1- (4- { [3- (morpholine -4- bases) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
3- (4- { [(2- chlorphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { 8- oxa- -3- azabicyclics [3.2.1] octane -3- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) Urea；
3- { 4- [4- (4- acetylphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(1H- indazole -6- bases) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3,4- Dimethoxyphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
N, N- dimethyl -3- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonamido] benzene first Acid amides；
1- (4- { [3- (cyclo propyl methoxy) phenyl] sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
(2R) -1- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] pyrrolidines -2- formyls Amine；
3- (4- { [(3- methoxyphenyls) methyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- picoline -3- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- [4- (ethylaminosulfonyl) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- fluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [2- (difluoro-methoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
1- (4- { 2- azabicyclics [2.2.1] heptane -2- sulfonyls } phenyl) -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3,5- dimethyl -1,2- oxazole -4- bases) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (pyridin-3-yl methyl) -3- (4- { 4- [5- (trifluoromethyl) pyridine -2- bases] piperazine -1- sulfonyls } phenyl) Urea；
3- [4- (2,3- dihydro -1H- indoles -1- sulfonyls) phenyl] -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- acetylphenyls) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(4- fluoro-2-methylbenzenes base) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [(4- cyano-phenyls) amino-sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 4- aminomethyl phenyls of 3-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3- chloro-5-methoxyls phenyl) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- (4- ((2- methoxy ethyls) (methyl) amino) piperidin-1-yl sulfonyl) phenyl) -3- (pyridin-3-yls Methyl) urea；
3- { 4- [(2,4- Dimethoxyphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (pyridin-3-yl methyl) -1- (4- { [2- (pyrrolidin-1-yl) phenyl] amino-sulfonyl } phenyl) urea；
3- { 4- [(3- methoxyl group -4- aminomethyl phenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (4- nitrobenzophenones) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (the chloro- 4- fluorophenoxies of 2-) piperidines -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- chloro- 2- (trifluoromethoxy) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the chloro- 3- aminomethyl phenyls of 4-) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2,3- dichlorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- (4- { [4- (propyl- 2- yls) phenyl] sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { imidazo [1,2-a] pyridine -6- ylmethyls } -1- (4- { 8- oxa- -3- azabicyclic [3.2.1] octanes -3- Sulfonyl } phenyl) urea；
The fluoro- N- of 2- (propyl- 2- yls) -5- [(4- { [(pyridin-3-yl methyl) carbamoyl] amino } phenyl) sulfonyl] Benzamide；
3- (4- { [2- (2- hydroxyl-oxethyls) phenyl] amino-sulfonyl } phenyl) -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2R, 6S) -2,6- thebaine -4- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(the fluoro- 2- methoxyphenyls of 4-) sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [4- (3- chlorphenyls) piperazine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2S) -2- ethyl piperidine -1- sulfonyls] phenyl } -1- (pyridin-3-yl methyl) urea；
1- (4- { [4- (morpholine -4- bases) phenyl] amino-sulfonyl } phenyl) -3- (pyridin-3-yl methyl) urea；
1- { 4- [(4- cyano-phenyls) sulfonyl] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(2- bromophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(3,4- 3,5-dimethylphenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
3- { 4- [(2- iodophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
1- { 4- [2- (morpholine -4- bases) pyridine -3- sulfonyls] phenyl } -3- (pyridin-3-yl methyl) urea；
3- { 4- [(3- fluorophenyls) amino-sulfonyl] phenyl } -1- (pyridin-3-yl methyl) urea；
N- { imidazo [1,2-a] pyridine -6- ylmethyls } -4- { [3- (trifluoromethoxy) phenyl] amino-sulfonyl } benzene first Acid amides；And
4- [(the chloro- 2- methoxyphenyls of 5-) amino-sulfonyl]-N- { imidazo [1,2-a] pyridine -6- ylmethyls } benzene first Acid amides；Or their pharmaceutical salts.
18. pharmaceutical composition, its compound comprising any one of item 1-17 and pharmaceutical carrier.
19. 18 pharmaceutical composition, also comprising chemotherapeutics.
20. 19 pharmaceutical composition, wherein the chemotherapeutics is DNA damage agent.
21. 18 pharmaceutical composition, also comprising cellular rescue agents.
22. 21 pharmaceutical composition, wherein the cellular rescue agents are selected from niacinamide, nicotinamide mononucleotide (NMN) And nicotinic acid.
23. 19 pharmaceutical composition, wherein the chemotherapeutics is selected from：Cytotoxic agent, cis-platinum, Doxorubicin, Tai Suo Supreme Being, PTX, Etoposide, Irinotecan, Irinotecan parenteral solution, Hycamtin, taxol, Docetaxel, Epothilones, TAM, 5 FU 5 fluorouracil, methotrexate (MTX), Temozolomide, endoxan, SCH 66336, for pyrrole method Buddhist nunR115777、L778,123、BMS 214662、C225、 Aromatase combination product, cytarabine, doxorubicin, cyclophosphamide system Agent, gemcitabine, uracil mustard, mustargen, ifosfamide, melphalan, Chlorambucil, pipobroman, tretamine, three Ethylidene thio-phosphamide, busulfan, BCNU, lomustine, streptozotocin, Dacarbazine, floxuridine, cytarabine, 6- Mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, folinic acid, oxaliplatinSpray department His fourth, vincaleukoblastinum, vincristine, eldisine, bleomycin, actinomycin D, daunorubicin, Doxorubicin, epirubicin, Idarubicin, plicamycin TM, deoxycoformycin, Mitomycin-C, L-ASP, Teniposide, the female alcohol of 17 alpha-acetylenes, Diethylstilbestrol, testosterone, metacortandracin, Fluoxymesterone, dromostanolone propionate, Testolactone, megestrol acetate, methylprednisolone, first testis Ketone, prednisolone, fluoxyprednisolone, Chlorotrianisene, hydroxyprogesterone, aminoglutethimide, Estramustine, medroxyprogesterone acetate, Leuprorelin, Flutamide, Toremifene, Goserelin, carboplatin, hydroxycarbamide, amsacrine, procarbazine, mitotane, mitoxantrone, left-handed miaow Azoles, NVB, Anastrozole, Letrozole, capecitabine, Raloxifene, Droloxifene, hexamidine, Avastin, He Sai Spit of fland, hectogram sand, Bortezomib, Ze Walin, trisenox, Xeloda, vinorelbine, porfimer, erbitux, liposome, thiophene are replaced Group, hemel, melphalan, trastuzumab, Letrozole, fulvestrant, Exemestane, ifosfamide, Rituximab, C225, Alemtuzumab, Calciumlevofolinate and dexamethasone, Bicalutamide, carboplatin, Chlorambucil, cis-platinum, Letrozole, megestrol acetate, Valrubicin and vincaleukoblastinum.
24. the pharmaceutical composition of any one of an any one of 1-17 compound or item 18-23, it is used for mammal In the middle method for suppressing abnormal cell growth or treating hyperproliferative disorders.
25. suppressing the method for nicotinamide phosphoribosyl transferase (" NAMPT ") in patient, it is effective by drug treatment Any one of at least one 1-17 of amount compound.
26. suppressing the method for NAMPT in patient, it passes through any one of at least one item 1-17 of drug treatment effective dose Compound.
27. by suppressing in patient NAMPT to treat, prevent, suppress or eliminate the disease or disease in the patient The method of disease, its by any one of at least one 1-17 of drug treatment effective dose compound, wherein the disease or Illness be selected from cancer, oophoroma, breast cancer, uterine cancer, colon cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, carcinoma of urinary bladder, Cancer of pancreas, leukaemia, lymthoma, Hodgkin's disease, viral infection, human immunodeficiency virus, hepatitis viruse, herpesviral, merely Bleb, inflammatory disorder, IBS, inflammatory bowel disease, rheumatoid arthritis, asthma, COPD, bone are closed Save inflammation, osteoporosis, dermatitis, atopic dermatitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis Inflammation, ankylosing spondylitis, graft versus host disease(GVH disease), Alzheimer disease, cerebrovas-cularaccident, atherosclerosis, diabetes, kidney Bead ephritis, metabolic syndrome, non-small cell lung cancer, ED-SCLC, Huppert's disease, leukaemia, lymthoma, squamous are thin Born of the same parents' cancer, kidney, Urinary Bladder cancer, head and neck cancer, brain and central nervous system cancer.
28. 27 method, wherein the disease is cancer.
29. 28 method, wherein the cancer is selected from leukaemia, lymthoma, oophoroma, breast cancer, uterine cancer, colon Cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, CNS cancers, carcinoma of urinary bladder, cancer of pancreas and Hodgkin's disease.
30. the pharmaceutical composition of any one of an any one of 1-17 compound or item 18-23 is moved for treating lactation The purposes of hyperproliferative disorders in thing.
31. 30 purposes, it is used for treating cancer.
32. the pharmaceutical composition of any one of an any one of 1-17 compound or item 18-23 is being prepared for treating Purposes in the medicine of cancer.
33. 31 or 32 purposes, wherein the cancer be selected from leukaemia, lymthoma, oophoroma, breast cancer, uterine cancer, Colon cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, CNS cancers, carcinoma of urinary bladder, cancer of pancreas and Hodgkin's disease.
Although cooperateing with the specific embodiment that is set forth above to describe the present invention, many alternatives, change and its Other versions will be obvious for those of ordinary skills.All this alternatives, change and Version is intended to fall in the spirit and scope of the invention.

Claims (10)

1. formula III A compounds and its pharmaceutical salts：
Wherein：
RaFor 1,2,3 or 4 and it may be selected from hydrogen, amino, oxo, halogen, alkoxy, alkyl, haloalkyl ,-N (alkyl)2、-NH (CO) O- alkyl, 1H- pyrazolyls, 1H- imidazole radicals and-C (O) NH2；And wherein described pyridine radicals can include by its N atom into The N- oxides that member is formed；
R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl and R4For alkyl, hydroxy alkyl ,-S (O)2Alkyl ,- (CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl；
Haloalkyl；
Cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；
The wherein each cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl for it is unsubstituted or by 1,2,3,4 or 5 substituents Substitution, the substituent is identical or different and is independently selected from：Halogen, cyano group, alkyl, hydroxyl, hydroxy alkyl, hydroxy alkoxy base, Haloalkyl, alkoxy, alkyl alkoxy, halogenated alkoxy, aryl alkenyl-, aryloxy, benzyl epoxide, oxo ,- (CH2)q-NRbRc、-(CH2)q-CONRbRc、-S(O)2- alkyl ,-S (O)2NH- alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2- CF3,-C (O) alkyl ,-C (O) aryl ,-C (O) alkenyl aryl ,-C (O) O- alkyl ,-(CH2)qCycloalkyl, cycloalkyl alkoxy-, Aryl, aryl alkyl-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl；
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, haloalkyl, haloalkoxies One or more of base, oxo, cyano group, alkyl, haloalkyl or alkoxy replace；
RbAnd RcIt is independently selected from H, alkyl, hydroxy alkyl, alkoxy, aryl, alkoxyalkyl ,-S (O)2Alkyl and cycloalkyl, or Person RbAnd Rc5 or 6 circle heterocycles alkyl are formed together with the nitrogen-atoms that can be connected with them, wherein the Heterocyclylalkyl can contain one Individual or multiple additional heteroatoms selected from N, S or O；
Q is 0 or 1；
Condition is that the formula III A compounds are not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea；
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide；Or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
2. the compound and its pharmaceutical salts of claim 1, wherein：
RaFor 1,2,3 or 4 and it may be selected from hydrogen, amino, oxo, halogen, (C1-C6) alkoxy, (C1-C6) alkyl, halo (C1- C6) alkyl ,-N (C1-C6- alkyl)2、-NH(CO)O-(C1-C6) alkyl, 1H- pyrazolyls, 1H- imidazole radicals and-C (O) NH2；And Wherein described pyridine radicals can include the N- oxides formed by its N atomic component；
R1For-NR3R4, wherein R3For H, C1-C6- alkyl or-S (O)2(C1-C6) alkyl, and R4For (C1-C6) alkyl, hydroxyl (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl (C1-C6) alkane Base-,-(CH2)qHeteroaryl；
Halo (C1-C6) alkyl；
C3-C12- cycloalkyl；
Aryl；
Heterocyclylalkyl；Or
Heteroaryl；
Wherein：
The each cycloalkyl, aryl or heteroaryl be unsubstituted or by 1,2,3,4 or 5 substituents replace, the substitution Base is identical or different and is independently selected from following：Halogen, cyano group, (C1-C6) alkyl, hydroxyl, hydroxyl (C1-C6) alkyl, hydroxyl (C1- C6) alkoxy, halo (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl (C1-C6) alkoxy, halo (C1-C6) alcoxyl Base, aryl (C2-C6) alkenyl-, aryloxy, benzyl epoxide, oxo ,-(CH2)q-NRbRc、-(CH2)q-CONRbRc、-S(O)2- (C1-C6) alkyl ,-S (O)2NH-(C1-C6) alkyl ,-S (O)2- Heterocyclylalkyl ,-S (O)2-CF3、-C(O)(C1-C6) alkyl ,-C (O) aryl ,-C (O) (C2-C6) alkenyl aryl ,-C (O) O- (C1-C6) alkyl ,-(CH2)qCycloalkyl, cycloalkyl (C1-C6) alcoxyl Base-, aryl, aryl (C1-C6) alkyl-,-(CH2)qHeteroaryl and-(CH2)qHeterocyclylalkyl,
The wherein each cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be by halogen, nitro, halo (C1-C6) alkyl, halogen Generation (C1-C6) alkoxy, oxo, cyano group, (C1-C6) alkyl, halo (C1-C6) alkyl or (C1-C6) one or many in alkoxy Individual substitution；
RbAnd RcIt is independently selected from H, (C1-C6) alkyl, hydroxyl (C1-C6) alkyl, (C1-C6) alkoxy, aryl, (C1-C6) alkoxy (C1-C6) alkyl ,-S (O)2(C1-C6) alkyl and (C3-C6) cycloalkyl, or RbAnd RcThe nitrogen-atoms one that can be connected with them Rise and form 5 or 6 circle heterocycles alkyl, wherein the Heterocyclylalkyl can contain one or more additional heteroatoms selected from N, S or O；
Q is 0 or 1；
Wherein Heterocyclylalkyl be containing 1, the heteroatomic 5-13 circle heterocycles alkyl that 2,3 or 4 are selected from N, O and S；Heteroaryl be containing Have 1, the heteroatomic 5-13 unit's heteroaryls that 2,3 or 4 are selected from N, O and S；And
Condition is that the formula III A compounds are not：
N- [4- (phenyl sulfonyl) phenyl]-N'- (3- pyridylmethyls) urea,
N, N- diethyl -4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide, or
4- [[[(3- pyridylmethyls) amino] carbonyl] amino] benzsulfamide.
3. the compound of claim 1 or 2, wherein R1For-NR3R4, wherein R3For H, alkyl or-S (O)2Alkyl, and R4For alkane Base, hydroxy alkyl ,-S (O)2Alkyl ,-(CH2)qCycloalkyl ,-(CH2)qHeterocyclylalkyl, aryl, aryl alkyl-,-(CH2)qHeteroaryl Base.
4. the compound of claim 3, wherein R1For-NR3R4, wherein R3For H, and R4For aryl.
5. pharmaceutical composition, its compound comprising any one of claim 1-4 and pharmaceutical carrier.
6. the pharmaceutical composition of claim 5, also comprising chemotherapeutics or cellular rescue agents.
7. any one of claim 1-3 compound is being prepared for suppressing nicotinamide phosphoribosyl transferase in patient Purposes in the medicine of (" NAMPT ").
8. the pharmaceutical composition of any one of any one of claim 1-3 compound or claim 5-6 is used in preparation For treating the purposes in mammal in the medicine of hyperproliferative disorders.
9. the pharmaceutical composition of any one of any one of claim 1-3 compound or claim 5-6 is used in preparation Purposes in the medicine for the treatment of cancer.
10. the purposes of claim 9, wherein the cancer is selected from leukaemia, lymthoma, oophoroma, breast cancer, uterine cancer, knot Intestinal cancer, cervical carcinoma, lung cancer, prostate cancer, cutaneum carcinoma, CNS cancers, carcinoma of urinary bladder, cancer of pancreas and Hodgkin's disease.
CN201610866074.2A 2010-09-03 2011-09-02 It is used as 4 { [(ylmethyl of pyridine 3) amino carbonyl] amino } Benzosulfone derivatives of the NAMPT inhibitor for treating diseases such as cancer Pending CN106986856A (en)

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